2,5-substituted oxazolopyrimidine derivatives

ABSTRACT

The invention relates to oxazolopyrimidine compounds of formula I, where A, R 1  and R 2  are defined as stated in the claims. The compounds of formula I are suitable, for example, for wound healing.

The present invention relates to 2,5-substituted oxazolopyrimidinederivatives, and to physiologically acceptable salts thereof.

Structurally similar compounds are already described in the prior art(see WO 2009/154775), which are suitable for treating multiplesclerosis. The mode of action of these compounds consists in causing adesensitization of the EDG-1 signal pathway by activating the EDG-1receptor (so-called superagonism), which is then equivalent to afunctional antagonism of the EDG-1 signal pathway. Systemically meansthat especially on lymphocytes, the EDG-1 signal pathway is permanentlysuppressed, as a result of which these cells can no longerchemotactically follow the S1P gradient between blood and lymph fluid.This means that the affected lymphocytes can no longer leave thesecondary lymphatic tissue (increased homing) and the number of freelycirculating lymphocytes in the plasma is greatly reduced. Thisdeficiency of lymphocytes in the plasma (lymphopenia) brings aboutimmunosuppression which is obligatorily required for the mechanism ofaction of the EDG-1 receptor modulators described in WO 2009/154775.

The object of the present invention was to provide compounds which aresuitable specifically for wound healing and in particular for thetreatment of wound healing disorders in patients with diabetes. Inaddition, it was desirable to provide compounds which are suitable forthe treatment of diabetic foot syndrome (DFS). Furthermore, it wasdesirable to achieve a reproducible activation of the EDG-1 receptorsignal pathway which thereby permits, in pharmacological terms, apersistent activation of the EDG-1 signal pathway.

The present invention relates to oxazolopyrimidine compounds of theformula I,

in which A, R¹ and R² are defined as indicated below. The mechanism ofaction of the compounds of the formula I is thus not based ondesensitization of the EDG-1 signal pathway and is therefore indiametral opposition to the mechanism of action described in WO2009/154775. The invention furthermore relates to processes for thepreparation of compounds of the formula I, their use, in particular asactive ingredients in pharmaceuticals, and pharmaceutical compositionscomprising them.

Compared with healthy people, patients with diabetes have delayed woundhealing and an increased rate of infection, especially in the case oflong-term hyperglycemia, caused for example by poor blood sugarregulation. The causes include circulation disorders, especially in thearea of the small vessels, which lead to impaired oxygen and nutrientsupply of the tissue. Moreover, the cell division and cell migrationrate of keratinocytes, fibroblasts and dermal endothelial cells isreduced. Additionally, the activity of various defense cells(granulocytes) with reduced phagocytosis (engulfing and destruction ofbacteria) is restricted. The function of the antibodies(immunoglobulins) against bacteria is also restricted in the event ofhigh blood sugar values. Accordingly, wounds and infections in patientswith diabetes have to be cared for in a particular way.

The Edg-1 receptor is a member of the endothelial differentiation gene(Edg) receptor family of currently eight identified class A GPCRs(G-protein coupled receptors). This family can be divided intosubfamilies of sphingosine-1-phosphate (S1P)-activated receptors (fivemembers) and receptors activated by lysophosphatidic acid (LPA; threemembers). The endogenous ligand S1P is a pluripotent lysophospholipidacting on different cell types by activating GPCRs from the Edg receptorfamily, namely Edg-1 (=S1P1), Edg-3 (=S1P3), Edg-5 (=S1P2), Edg-6(=S1P4) and Edg-8 (S1P5). Although S1P is also described as anintracellular messenger, numerous cellular responses of S1P are mediatedvia the activation of Edg receptors. S1P is generated by the enzymefamily of sphingosine kinases (SPHK) and degraded by differentphosphatases or lyases.

A subject of the present invention is an oxazolopyrimidine compound ofthe formula I, in any of its stereoisomeric forms, or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof, or a physiologically acceptable solvate of any of them,

wherein

A is chosen from NH, O and S;

R¹ is chosen from (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,(C₃-C₇)-cycloalkyl-C_(u)H_(2u)— and Het-C_(v)H_(2v)—, wherein u and vare chosen from 1 and 2, or R¹ is a residue of a saturated orunsaturated, 3-membered to 10-membered, monocyclic or bicyclic ringwhich comprises 0, 1, 2, 3 or 4 identical or different ring heteroatomschosen from N, O and S, wherein one or two of the ring nitrogen atomscan carry a hydrogen atom or a (C₁-C₄)-alkyl substituent and one or twoof the ring sulfur atoms can carry one or two oxo groups, and whereinthe residue of a ring is optionally substituted on one or more ringcarbon atoms by identical or different substituents R¹¹;

R² is chosen from phenyl and a residue of an aromatic, 5-membered to6-membered monocyclic heterocycle which comprises 1, 2 or 3 identical ordifferent ring heteroatoms chosen from N, O and S, wherein one of thering nitrogen atoms can carry a hydrogen atom or a substituent R²¹, andwherein the phenyl and residue of an aromatic heterocycle are optionallysubstituted on one or more ring carbon atoms by identical or differentsubstituents R²²;

R¹¹ is chosen from halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, hydroxy,(C₁-C₄)-alkyloxy, oxo, (C₁-C₄)-alkyl-S(O)_(m)—, amino,(C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, (C₁-C₄)-alkylcarbonylamino,(C₁-C₄)-alkylsulfonylamino, nitro, cyano, (C₁-C₄)-alkylcarbonyl,aminosulfonyl, (C₁-C₄)-alkylaminosulfonyl anddi((C₁-C₄)-alkyl)aminosulfonyl;

R²¹ is chosen from (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl-C_(w)H_(2w)— andoxy, wherein w is chosen from 0, 1 and 2;

R²² is chosen from halogen, hydroxy, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy,(C₁-C₄)-alkyl-S(O)_(m)-, amino, nitro, cyano, hydroxycarbonyl,(C₁-C₄)-alkyloxycarbonyl, aminocarbonyl, aminosulfonyl, R²³ and R²³—O—;

R²³ is a residue of a saturated 3-membered to 7-membered, monocyclic orbicyclic ring which comprises 0, 1, 2, 3 or 4 identical or differentring heteroatoms chosen from N, O and S, wherein one or two of the ringnitrogen atoms can carry a hydrogen atom or a (C₁-C₄)-alkyl substituentand one of the ring sulfur atoms can carry one or two oxo groups, andwherein the residue of a ring is optionally substituted on one or morering carbon atoms by identical or different substituents R²⁴;

R²⁴ is chosen from halogen, (C₁-C₄)-alkyl, hydroxy and oxo;

Het is a residue of a saturated, 4-membered to 7-membered, monocyclicheterocycle which comprises 1 or 2 identical or different ringheteroatoms chosen from N, O and S and which is bonded via a ring carbonatom, wherein the residue of a heterocycle is optionally substituted byone or more identical or different substituents chosen from fluorine and(C₁-C₄)-alkyl;

m is chosen from 0, 1 and 2, wherein all numbers m are independent ofeach other; wherein all cycloalkyl groups, independently of each otherand independently of any other substituents, are optionally substitutedby one or more identical or different substituents chosen from fluorineand (C₁-C₄)-alkyl;

wherein all alkyl, C_(u)H_(2u), C_(v)H_(2v), C_(w)H_(2w), alkenyl andalkynyl groups, independently of each other and independently of anyother substituents, are optionally substituted by one or more fluorinesubstituents.

Structural elements such as groups, substituents, hetero ring members,numbers or other features, for example alkyl groups, groups like R²² orR¹¹, numbers like m, u and v, which can occur several times in thecompounds of the formula I, can all independently of one another haveany of the indicated meanings and can in each case be identical to ordifferent from one another. For example, the alkyl groups in adialkylamino group can be identical or different.

Alkyl, alkenyl and alkynyl groups can be linear, i.e. straight-chain, orbranched. This also applies when they are part of other groups, forexample alkyloxy groups (=alkoxy groups, alkyl-O— groups),alkyloxycarbonyl groups or alkyl-substituted amino groups, or when theyare substituted. Depending on the respective definition, the number ofcarbon atoms in an alkyl group can be 1, 2, 3, 4, 5 or 6, or 1, 2, 3 or4, or 1, 2 or 3. Examples of alkyl are methyl, ethyl, propyl includingn-propyl and isopropyl, butyl including n-butyl, sec-butyl, isobutyl andtert-butyl, pentyl including n-pentyl, 1-methylbutyl, isopentyl,neopentyl and tert-pentyl, and hexyl including n-hexyl,3,3-dimethylbutyl and isohexyl. Double bonds and triple bonds in alkenylgroups and alkynyl groups can be present in any positions. In oneembodiment of the invention, alkenyl groups contain one double bond andalkynyl groups contain one triple bond. In one embodiment of theinvention, an alkenyl group or alkynyl group contains at least threecarbon atoms and is bonded to the remainder of the molecule via a carbonatom which is not part of a double bond or triple bond. Examples ofalkenyl and alkynyl are ethenyl, prop-1-enyl, prop-2-enyl (=allyl),but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl,hex-4-enyl, prop-2-ynyl (=propargyl), but-2-ynyl, but-3-ynyl, hex-4-ynylor hex-5-ynyl. Substituted alkyl groups, alkenyl groups and alkynylgroups can be substituted in any positions, provided that the respectivecompound is sufficiently stable and is suitable for the desired purposesuch as use as a drug substance. The prerequisite that a specific groupand a compound of the formula I are sufficiently stable and suitable forthe desired purpose such as use as a drug substance, applies in generalwith respect to the definitions of all groups in the compounds of theformula I.

As far as applicable, the preceding explanations regarding alkyl groupsapply correspondingly to divalent alkyl groups such as the groupsC_(u)H_(2u), C_(v)H_(2v) and C_(w)H_(2w), which thus can likewise belinear and branched. Examples of divalent alkyl groups are —CH₂—(=methylene), —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH(CH₃)—, —C(CH₃)₂—,—CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—. If a number in a divalent group such asthe number u in the group C_(u)H_(2u), for example, is 0 (=zero), thetwo groups which are attached to the contemplated group, such asC_(u)H_(2u), are directly connected to one another via a single bond.

The number of ring carbon atoms in a cycloalkyl group can be 3, 4, 5, 6or 7. In one embodiment of the invention, the number of ring carbonatoms in a cycloalkyl group, independently of the number of ring carbonatoms in any other cycloalkyl group, is 3, 4, 5 or 6, in anotherembodiment 3, 4 or 5, in another embodiment 3 or 4, in anotherembodiment 3, in another embodiment 5, 6 or 7, in another embodiment 5or 6, in another embodiment 6 or 7, in another embodiment 6. Examples ofcycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl. Independently of one another and independently of anyother substituents, cycloalkyl groups are optionally substituted by oneor more identical or different (C₁-C₄)-alkyl substituents which can belocated in any positions, i.e., cycloalkyl groups can be unsubstitutedby alkyl substituents or substituted by alkyl substituents, for exampleby 1, 2, 3 or 4, or by 1 or 2, (C₁-C₄)-alkyl substituents, for exampleby methyl groups. Examples of alkyl-substituted cycloalkyl groups are4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclopentyl.Examples of cycloalkylalkyl groups, which can represent groups such as(C₃-C₇)-cycloalkyl, for example, are cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,cycloheptylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl,1-cyclobutylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl,2-cyclohexylethyl, 2-cycloheptylethyl.

Independently of one another and independently of any othersubstituents, alkyl groups, divalent alkyl groups, alkenyl groups,alkynyl groups and cycloalkyl groups are optionally substituted by oneor more fluorine substituents which can be located in any positions,i.e., the said groups can be unsubstituted by fluorine substituents orsubstituted by fluorine substituents, for example by 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12 or 13, or by 1, 2, 3, 4, 5, 6, 7, 8 or 9, or by 1,2, 3, 4, 5, 6 or 7, or by 1, 2, 3, 4 or 5, or by 1, 2 or 3, or by 1 or2, fluorine substituents. Examples of fluorine-substituted said groupsare trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl,4,4,4-trifluorobutyl, heptafluoroisopropyl, —CHF—, —CF₂—, —CF₂—CH₂—,—CH₂—CF₂—, —CF₂—CF₂—, —CF(CH₃)—, —C(CF₃)₂—, 1-fluorocyclopropyl,2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl, 1-fluorocyclohexyl,4,4-difluorocyclohexyl, 3,3,4,4,5,5-hexafluorocyclohexyl. Examples ofalkyloxy groups in which the alkyl moiety is fluorine-substituted, aretrifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and3,3,3-trifluoropropoxy. In one embodiment of the invention, the totalnumber of fluorine substituents and (C₁-C₄)-alkyl substituents, whichindependently of any other substituents are optionally present oncycloalkyl groups in the compounds of the formula I, is 1, 2, 3, 4, 5,6, 7, 8, 9, 10 or 11, in another embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9,in another embodiment 1, 2, 3, 4 or 5, in another embodiment 1, 2, 3 or4.

Groups like phenyl, naphthyl (=naphthalenyl) and residues of aromaticheterocycles which are optionally substituted by one or moresubstituents, can be unsubstituted or substituted, for example by 1, 2,3, 4 or 5, or by 1, 2, 3 or 4, or by 1, 2 or 3, or by 1 or 2, or by 1,identical or different substituents which can be located in anypositions. In one embodiment of the invention the total number of nitrosubstituents in a compound of the formula I is not greater than two.Aromatic nitrogen heterocycles which in the parent ring system carry ahydrogen atom on a ring nitrogen atom in a 5-membered ring, such as apyrrole, imidazole, indole or benzoimidazole ring, for example, can besubstituted on the carbon atoms and/or on such ring nitrogen atoms. Inone embodiment of the invention, substituents on such ring nitrogenatoms are chosen from (C₁-C₄)-alkyl groups, i.e. such ring nitrogenatoms in aromatic heterocycles carry a hydrogen atom or a (C₁-C₄)-alkylsubstituent. When it is stated with respect to ring nitrogen atoms inaromatic heterocycles and any other heterocycles that they can carry ahydrogen atom or a substituent, such ring nitrogen atoms either carry ahydrogen atom or a substituent, or they do not carry a hydrogen atom orsubstituent. Ring nitrogen atoms which carry a hydrogen atom or asubstituent, occur in a nitrogen-containing aromatic 5-membered ring asis present in pyrrole, imidazole, indole or benzoimidazole, for example,and in a non-aromatic ring including a saturated ring. Ring nitrogenatoms which do not carry a hydrogen atom or a substituent unless theyare present in positively charged form, including any further ringnitrogen atoms in addition to ring nitrogen atoms which carry a hydrogenatom or a substituent, occur in an aromatic ring as is present inthiazole, imidazole, pyridine or benzoimidazole, for example, and in anon-aromatic ring in which they are bridgehead atoms or are part of adouble bond, and they occur as ring nitrogen atoms via which a ring isbonded. Suitable ring nitrogen atoms in aromatic heterocycles in thecompounds of the formula I, such as the ring nitrogen atom in a pyridinering, specifically a ring nitrogen atom in an aromatic heterocyclerepresenting R², can also carry an oxy substituent and be present as anN-oxide, and such ring nitrogen atoms can also be present as quaternarysalt, for example as N—(C₁-C₄)-alkyl salt such as N-methyl salt, whereinin one embodiment of the invention the counter anion in such quaternarysalt is a physiologically acceptable anion which is derived from an acidthat forms a physiologically acceptable salt. In monosubstituted phenylgroups, the substituent can be located in the 2-position, the 3-positionor the 4-position. In disubstituted phenyl groups, the substituents canbe located in 2,3-position, 2,4-position, 2,5-position, 2,6-position,3,4-position or 3,5-position. In trisubstituted phenyl groups, thesubstituents can be located in 2,3,4-position, 2,3,5-position,2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position.Naphthyl can be 1-naphthyl (=naphthalen-1-yl) or 2-naphthyl(=naphthalen-2-yl). In monosubstituted 1-naphthyl groups, thesubstituent can be located in the 2-, 3-, 4-, 5-, 6-, 7- or 8-position.In monosubstituted 2-naphthyl groups, the substituent can be located inthe 1-, 3-, 4-, 5-, 6-, 7- or 8-position. In disubstituted naphthylgroups, the substituents can likewise be located in any positions bothin the ring via which the naphthyl group is bonded and/or in the otherring.

In residues of aromatic heterocycles representing R¹ or R², which may bedesignated as heteroaryl groups, as well as in all other heterocyclicrings in the compounds of the formula I including the group Het andnon-aromatic heterocyclic groups representing R¹, the ring heteroatomsare generally chosen from N, O and S, wherein N includes ring nitrogenatoms which carry a hydrogen atom or a substituent as well as ringnitrogen atoms which do not carry a hydrogen atom or a substituent. Ringheteroatoms can be located in any positions, provided that theheterocyclic system is known in the art and is stable and suitable as asubgroup for the desired purpose of the compound of the formula I suchas use as a drug substance. In one embodiment of the invention, two ringoxygen atoms cannot be present in adjacent ring positions of anyheterocycle, in another embodiment two ring heteroatoms chosen fromoxygen and sulfur cannot be present in adjacent ring positions of anyheterocycle. Saturated rings do not contain a double bond within thering. Unsaturated ring systems can be aromatic or partially unsaturatedincluding partially aromatic, in which latter case one ring in abicyclic ring system is aromatic and the ring system is bonded via anatom in the non-aromatic ring. Depending on the respective group,unsaturated rings can contain one, two, three, four or five double bondswithin the ring. Aromatic groups contain a cyclic system of six or tendelocalized pi electrons in the ring. Depending on the respective group,saturated and non-aromatic unsaturated heterocyclic rings, including Hetand non-aromatic groups representing R¹, can be 3-membered, 4-membered,5-membered, 6-membered, 7-membered, 8-membered, 9-membered or10-membered. In one embodiment of the invention, aromatic heterocyclicrings are 5-membered or 6-membered monocyclic rings or 8-membered,9-membered or 10-membered bicyclic rings, in another embodiment5-membered or 6-membered monocyclic rings or 9-membered or 10-memberedbicyclic rings, in another embodiment 5-membered or 6-memberedmonocyclic rings, wherein the 8-membered, 9-membered or 10-memberedbicyclic rings are composed of two fused 5-membered rings, a 5-memberedring and a 6-membered ring which are fused to one another, and two fused6-membered rings, respectively. In bicyclic aromatic heterocyclicgroups, one or both rings can contain hetero ring members, and one orboth rings can be aromatic. In general, bicyclic ring systems containingan aromatic ring and a non-aromatic ring are regarded as aromatic whenthey are bonded via a carbon atom in the aromatic ring, and asnon-aromatic when they are bonded via a carbon atom in the non-aromaticring. Unless stated otherwise, heterocyclic groups including aromaticheterocyclic groups can be bonded via any suitable ring carbon atom and,in the case of nitrogen heterocycles, via any suitable ring nitrogenatom. In one embodiment of the invention, an aromatic heterocyclic groupin a compound of the formula I, independently of any other aromaticheterocyclic group, is bonded via a ring carbon atom, in anotherembodiment via a ring nitrogen atom. Depending on the definition of therespective heterocyclic group, in one embodiment of the invention thenumber of ring heteroatoms which can be present in a heterocyclic group,independently of the number of ring heteroatoms in any otherheterocyclic group, is 1, 2, 3 or 4, in another embodiment 1, 2 or 3, inanother embodiment 1 or 2, in another embodiment 1, wherein the ringheteroatoms can be identical or different. Heterocyclic groups which areoptionally substituted, can independently of any other heterocyclicgroup be unsubstituted or substituted by one or more identical ordifferent substituents, for example by 1, 2, 3, 4 or 5, or by 1, 2, 3 or4, or by 1, 2 or 3, or by 1 or 2, or by 1 substituents, which areindicated in the definition of the respective group. Substituents onheterocyclic groups can be located in any positions. For example, in apyridin-2-yl group substituents can be located in the 3-position and/or4-position and/or 5-position and/or 6-position, in a pyridin-3-yl groupsubstituents can be located in the 2-position and/or 4-position and/or5-position and/or 6-position, in a pyridin-4-yl group substituents canbe located in the 2-position and/or 3-position and/or 5-position and/or6-position.

Examples of parent heterocycles, from which heterocyclic groupsincluding aromatic heterocyclic groups, saturated heterocyclic groupsand non-aromatic unsaturated heterocyclic groups can be derived, areazete, oxete, pyrrole, furan, thiophene, imidazole, pyrazole,[1,3]dioxole, oxazole (=[1,3]oxazole), isoxazole (=[1,2]oxazole),thiazole (=[1,3]thiazole), isothiazole (=[1,2]thiazole),[1,2,3]triazole, [1,2,4]triazole, [1,2,4]oxadiazole, [1,3,4]oxadiazole,[1,2,4]thiadiazole, [1,3,4]thiadiazole, tetrazole, pyridine, pyran,thiopyran, pyridazine, pyrimidine, pyrazine, [1,3]oxazine, [1,4]oxazine,[1,3]thiazine, [1,4]thiazine, [1,2,3]triazine, [1,3]dithiine,[1,4]dithiine, [1,2,4]triazine, [1,3,5]triazine, [1,2,4,5]tetrazine,azepine, [1,3]diazepine, [1,4]diazepine, [1,3]oxazepine, [1,4]oxazepine,[1,3]thiazepine, [1,4]thiazepine, azocine, azecine,cyclopenta[b]pyrrole, 2-azabicyclo[3.1.0]hexane,3-azabicyclo[3.1.0]hexane, 2-oxa-5-azabicyclo[2.2.1]heptane, indole,isoindole, benzothiophene, benzofuran, [1,3]benzodioxole(=1,2-methylenedioxybenzene), [1,3]benzoxazole, [1,3]benzothiazole,benzoimidazole, thieno[3,2-c]pyridine, chromene, isochromene,[1,4]benzodioxine, [1,4]benzoxazine, [1,4]benzothiazine, quinoline,isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine,thienothiophene, [1,8]naphthyridine and other naphthyridines, pteridine,and the respective saturated and partially unsaturated heterocycles inwhich one or more, for example one, two, three, four or all double bondswithin the ring system including double bonds in aromatic ring arereplaced with single bonds, such as azetidine, oxetane, pyrrolidine,tetrahydrofuran, tetrahydrothiophene, imidazolidine, oxazolidine,thiazolidine, dihydropyridine, piperidine, tetrahydropyran, piperazine,morpholine, thiomorpholine, azepane, chroman, isochroman,[1,4]benzodioxane (=1,2-ethylenedioxybenzene), 2,3-dihydrobenzofuran,1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, forexample.

Examples of residues of aromatic heterocycles, which can occur in thecompounds of the formula I, are thiophenyl (=thienyl) includingthiophen-2-yl and thiophen-3-yl, pyridinyl (=pyridyl) includingpyridin-2-yl (=2-pyridyl), pyridin-3-yl (=3-pyridyl) and pyridin-4-yl(=4-pyridyl), imidazolyl including, for example, 1H-imidazol-1-yl,1H-imidazol-2-yl, 1H-imidazol-4-yl and 1H-imidazol-5-yl,[1,2,4]triazolyl including 1H-[1,2,4]-triazol-1-yl and4H-[1,2,4]-triazol-3-yl, tetrazolyl including 1H-tetrazol-1-yl and1H-tetrazol-5-yl, quinolinyl (=quinolyl) including quinolin-2-yl,quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl,quinolin-7-yl and quinolin-8-yl, which all are optionally substituted asindicated in the definition of the respective group. Examples ofresidues of saturated and partially unsaturated heterocycles, which canoccur in the compounds of the formula I, are azetidinyl, pyrrolidinylincluding pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl,2,5-dihydro-1H-pyrrolyl, piperidinyl including piperidin-1-yl,piperidin-2-yl, piperidin-3-yl and piperidin-4-yl,1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl,1,2-dihydropyridinyl, azepanyl, azocanyl, azecanyl,octahydrocyclopenta[b]pyrrolyl, 2,3-dihydrobenzofuranyl including2,3-dihydrobenzofuran-7-yl, 2,3-dihydro-1H-indolyl,octahydro-1H-indolyl, 2,3-dihydro-1H-isoindolyl,octahydro-1H-isoindolyl, 1,2-dihydroquinolinyl,1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl,1,2-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, decahydroisoquinolinyl,decahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl,pyrazolidinyl, imidazolidinyl, hexahydropyrimidinyl,1,2-dihydropyrimidinyl, piperazinyl, [1,3]diazepanyl, [1,4]diazepanyl,oxazolidinyl, [1,3]oxazinanyl, [1,3]oxazepanyl, morpholinyl includingmorpholin-2-yl, morpholin-3-yl and morpholin-4-yl, [1,4]oxazepanyl,thiazolidinyl, [1,3]thiazinanyl, thiomorpholinyl includingthiomorpholin-2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl,3,4-dihydro-2H-[1,4]thiazinyl, [1,3]thiazepanyl, [1,4]thiazepanyl,[1,4]thiazepanyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl,isoxazolidinyl, isothiazolidinyl, oxazolidinyl, [1,2,4]-oxadiazolidinyl,[1,2,4]-thiadiazolidinyl, [1,2,4]triazolidinyl, [1,3,4]oxadiazolidinyl,[1,3,4]thiadiazolidinyl, [1,3,4]triazolidinyl, 2,3-dihydrofuranyl,2,5-dihydrofuranyl, 2,3-dihydrothienyl, 2,5-dihydrothienyl,2,3-dihydropyrrolyl, 2,3-dihydroisoxazolyl, 4,5-dihydroisoxazolyl,2,5-dihydroisoxazolyl, 2,3-dihydroisothiazolyl, 4,5-dihydroisothiazolyl,2,5-dihydroisothiazolyl, 2,3-dihydropyrazolyl, 4,5-dihydropyrazolyl,2,5-dihydropyrazolyl, 2,3-dihydrooxazolyl, 4,5-dihydrooxazolyl,2,5-dihydrooxazolyl, 2,3-dihydrothiazolyl, 4,5-dihydrothiazolyl,2,5-dihydrothiazolyl, 2,3-dihydroimidazolyl, 4,5-dihydroimidazolyl,2,5-dihydroimidazolyl, tetrahydropyridazinyl, tetrahydropyrimidinyl,tetrahydropyrazinyl, tetrahydro[1,3,5]triazinyl, [1,3]dithianyl,tetrahydropyranyl, tetrahydrothiopyranyl, [1,3]dioxolanyl,3,4,5,6-tetrahydropyridinyl, 4H-[1,3]thiazinyl,1,1-dioxo-2,3,4,5-tetrahydrothienyl, 2-azabicyclo[3.1.0]hexyl including2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.1.0]hexyl including3-azabicyclo[3.1.0]hex-3-yl, 2-oxa-5-azabicyclo[2.2.1]-heptyl including2-oxa-5-azabicyclo[2.2.1]-hept-5-yl, which all are bonded via anysuitable ring carbon atom or ring nitrogen atom and are optionallysubstituted as indicated in the definition of the respective group.

Halogen is fluorine, chlorine, bromine or iodine. In one embodiment ofthe invention, any halogen in a compound of the formula I isindependently of any other halogen chosen from fluorine, chlorine andbromine, in another embodiment from fluorine and chlorine.

When an oxo group is bonded to a carbon atom, it replaces two hydrogenatoms on a carbon atom of the parent system. Thus, if a CH₂ group in achain or a ring is substituted by oxo, i.e. by a doubly bonded oxygenatom, it becomes a C(O)(═C(═O)) group. Evidently, an oxo group cannotoccur as a substituent on a carbon atom in an aromatic ring such as in aphenyl group, for example. When a ring sulfur atom in a heterocyclicgroup can carry one or two oxo groups, it is a non-oxidized sulfur atomS in case it does not carry any oxo group, or it is an S(O) group(=sulfoxide group, S-oxide group) in case it carries one oxo group, orit is an S(O)₂ group (=sulfone group, S,S-dioxide group) in case itcarries two oxo groups.

The present invention includes all stereoisomeric forms of the compoundsof the formula I and their salts and solvates. With respect to eachchiral center, independently of any other chiral center, the compoundsof the formula I can be present in S configuration or substantially Sconfiguration, or in R configuration or substantially R configuration,or as a mixture of the S isomer and the R isomer in any ratio. Theinvention includes all possible enantiomers and diastereomers andmixtures of two or more stereoisomers, for example mixtures ofenantiomers and/or diastereomers, in all ratios. Thus, compoundsaccording to the invention which can exist as enantiomers can be presentin enantiomerically pure form, both as levorotatory and asdextrorotatory antipodes, and in the form of mixtures of the twoenantiomers in all ratios including racemates. In the case of a E/Zisomerism, or cis/trans isomerism, for example on double bonds or ringssuch as cycloalkyl rings, the invention includes both the E form and Zform, or the cis form and the trans form, as well as mixtures of theseforms in all ratios. In one embodiment of the invention, a compoundwhich can occur in two or more stereoisomeric forms is a pure, orsubstantially pure, individual stereoisomer. The preparation ofindividual stereoisomers can be carried out, for example, by separationof a mixture of isomers by customary methods, for example bychromatography or crystallization, by the use of stereochemicallyuniform starting materials in the synthesis, or by stereoselectivesynthesis. Optionally, a derivatization can be carried out before aseparation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at the stage of the compound of theformula I or at the stage of a starting material or an intermediateduring the synthesis. The present invention also includes all tautomericforms of the compounds of the formula I and their salts and solvates.

In case the compounds of the formula I contain one or more acidic and/orbasic groups, i.e. salt-forming groups, the invention also includestheir corresponding physiologically or toxicologically acceptable salts,i.e. non-toxic salts, in particular their pharmaceutically acceptablesalts. Thus, the compounds of the formula I which contain an acidicgroup, such as a hydroxycarbonyl group (=carboxy group=C(O)—OH group),can be present on such groups, and can be used according to theinvention, as alkaline metal salts, alkaline earth metal salts or asammonium salts, for example. More specific examples of such saltsinclude sodium salts, potassium salts, calcium salts, magnesium salts,quaternary ammonium salts such as tetraalkylammonium salts, or acidaddition salts with ammonia or organic amines such as, for example,ethylamine, ethanolamine, triethanolamine or amino acids. Compounds ofthe formula I which contain a basic group, i.e. a group which can beprotonated such as an amino group or a nitrogen heterocycle, can bepresent on such groups, and can be used according to the invention, inthe form of their addition salts with inorganic and organic acids.Examples of suitable acids include hydrogen chloride, hydrogen bromide,phosphoric acid, sulfuric acid, methanesulfonic acid, oxalic acid,acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, benzoicacid, malonic acid, fumaric acid, maleic acid, citric acid, and otheracids known to the person skilled in the art. If a compound of theformula I simultaneously contains an acidic group and a basic group inthe molecule, the compound also includes, in addition to the salt formsmentioned, inner salts (=betaines, zwitterions). The salts of thecompounds of the formula I can be obtained by customary methods whichare known to the person skilled in the art like, for example, bycontacting the compound of the formula I with an organic or inorganicacid or base in a solvent or diluent, or by anion exchange or cationexchange from another salt. The invention also includes all salts of thecompounds of the formula I which, owing to low physiologicalcompatibility of the salt-forming acid or base, are not directlysuitable for use in pharmaceuticals but which can be used, for example,as intermediates for chemical reactions or for the preparation ofphysiologically acceptable salts.

The present invention furthermore includes all solvates of compounds ofthe formula I, for example hydrates or adducts with alcohols such as(C₁-C₄)-alkanols, active metabolites of the compounds of the formula I,and also prodrugs and derivatives of the compounds of the formula Iwhich in vitro may not necessarily exhibit pharmacological activity butwhich in vivo are converted into pharmacologically active compounds, forexample esters or amides of carboxylic acid groups.

In one embodiment of the invention, A is chosen from NH and O, inanother embodiment, A is chosen from NH and S, in another embodiment Ais chosen from O and S, in another embodiment A is NH, in anotherembodiment A is O, in another embodiment A is S.

In one embodiment of the invention, R¹ is chosen from (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl and (C₂-C₆)-alkynyl, in another embodiment R¹ is(C₁-C₆)-alkyl, in another embodiment R¹ is (C₂-C₅)-alkyl, and in anotherembodiment R¹ is (C₁-C₄)-alkyl, provided that R¹ cannot be an alkylgroup if A is S. In another embodiment R¹ is chosen from (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl-C_(u)H_(2u)— and Het-C_(v)H_(2v)—, in anotherembodiment from (C₃-C₇)-cycloalkyl-C_(u)H_(2u)— and Het-C_(v)H_(2v)—, inanother embodiment R¹ is (C₃-C₇)-cycloalkyl-C_(u)H_(2u)—, and in anotherembodiment R¹ is Het-C_(v)H_(2v)—, wherein in this embodiment u and vindependently of each other are chosen from 1 and 2. In one embodiment uis 1, in another embodiment u is 2. In one embodiment v is 1, in anotherembodiment v is 2. In one embodiment, the group(C₃-C₇)-cycloalkyl-C_(u)H_(2u)-representing R¹ is chosen fromcyclopropyl-C_(u)H_(2u)—, cyclobutyl-C_(u)H_(2u)— andcyclopentyl-C_(u)H_(2u).

In one embodiment, R¹ is chosen from (C₃-C₇)-cycloalkyl-C_(u)H_(2u)— andHet-C_(v)H_(2v)—, or R³ is a residue of a saturated or unsaturated,3-membered to 10-membered, monocyclic or bicyclic ring which comprises0, 1, 2, 3 or 4 identical or different ring heteroatoms chosen from N, Oand S, wherein one or two of the ring nitrogen atoms can carry ahydrogen atom or a (C₁-C₄)-alkyl substituent and one or two of the ringsulfur atoms can carry one or two oxo groups, and wherein the residue ofa ring is optionally substituted on one or more ring carbon atoms byidentical or different substituents R¹¹, and in another embodiment R¹ isa residue of a saturated or unsaturated, 3-membered to 10-membered,monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or 4 identical ordifferent ring heteroatoms chosen from N, O and S, wherein one or two ofthe ring nitrogen atoms can carry a hydrogen atom or a (C₁-C₄)-alkylsubstituent and one or two of the ring sulfur atoms can carry one or twooxo groups, and wherein the residue of a ring is optionally substitutedon one or more ring carbon atoms by identical or different substituentsR¹¹. In one embodiment, the number of ring heteroatoms in the ringrepresenting R¹ is 0, 1, 2 or 3, in another embodiment it is 0, 1 or 2,in another embodiment it is 0 or 1, in another embodiment it is 0, inanother embodiment it is 1, 2, 3 or 4, in another embodiment it is 1, 2or 3, in another embodiment it is 1 or 2, in another embodiment it is 1.The residue of the ring representing R¹ can thus be carbocyclic orheterocyclic. In one embodiment, the ring heteroatoms in R¹ are chosenfrom N and O, in another embodiment from N and S, in another embodimentfrom O and S, in another embodiment they are N, wherein ring nitrogenatoms can carry a hydrogen atom or a (C₁-C₄)-alkyl substituent as occursin saturated or partially unsaturated heterocycles or in 5-memberedaromatic rings in heterocycles such as pyrrole or benzoimidazole, forexample, or not carry a hydrogen atom or a (C₁-C₄)-alkyl substituent asoccurs in aromatic heterocycles such as imidazole or pyridine, forexample. In a residue of a heterocycle representing R¹ which comprisesone or more ring sulfur atoms, in one embodiment one of the ring sulfuratoms is non-oxidized or carries one or two oxo groups, and any otherring sulfur atoms are non-oxidized. The residue of a monocyclic orbicyclic ring representing R¹ can be bonded to the group A via anysuitable ring carbon atom or ring nitrogen atom. In one embodiment it isbonded via a ring carbon atom, in another embodiment it is bonded via aring carbon atom or, in case A is NH, via a ring nitrogen atom, and inanother embodiment it is bonded via a ring nitrogen atom. The residue ofa monocyclic or bicyclic ring representing R¹ can be unsaturated and inthis case contain 1, 2, 3, 4 or 5, or 1, 2, 3 or 4, or 1, 2 or 3, or 1or 2, or 1, double bonds within the ring and can in any of the one ortwo rings be aromatic or non-aromatic, or it can be saturated and inthis latter case contain no double bonds within the ring. In oneembodiment, the residue of the ring representing R¹ is saturated oraromatic, in another embodiment it is saturated, and in anotherembodiment it is aromatic. In one embodiment, the residue of 3-memberedor 4-membered ring representing R¹ is saturated. If R¹ comprises ringnitrogen atoms which can carry a hydrogen atom or a (C₁-C₄)-alkylsubstituent, one of such ring nitrogen atoms or two of such ringnitrogen atoms can be present. In one embodiment, the number of optionalsubstituents R¹¹ on ring carbon atoms in the ring representing R¹ is 1,2, 3, 4, 5 or 6, in another embodiment 1, 2, 3, 4 or 5, in anotherembodiment 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in anotherembodiment 1 or 2, in another embodiment 1.

The ring which can represent R¹ can be 3-membered, 4-membered,5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10membered. In one embodiment, R¹ is 4-membered to 10-membered, in anotherembodiment 4-membered to 9-membered, in another embodiment 4-membered to8-membered, in another embodiment 4-membered to 7-membered, in another5-membered to 7-membered, in another embodiment 5-membered or6-membered, in another embodiment 6-membered, in another embodiment8-membered to 10-membered, in another embodiment 9-membered to10-membered. In one embodiment, a 3-membered ring representing R¹ doesnot comprise any ring heteroatoms. In one embodiment, R¹ is monocyclic,in another embodiment bicyclic. In one embodiment, a bicyclic grouprepresenting R¹ is at least 7-membered. Among others, the residue of aring representing R¹ can be a cycloalkyl group, a phenyl group, anaphthyl group, a residue of an unsaturated, aromatic or non-aromaticheterocyclic group or a residue of a saturated heterocyclic group, whichall are optionally substituted on ring carbon atoms and ring nitrogenatoms as specified with respect to R¹. As far as applicable, allexplanations given above with respect to such groups applycorrespondingly to R¹. Another example of groups which can represent R¹,are cycloalkenyl groups such as (C₅-C₇)-cycloalkenyl groups which can bebonded via any ring carbon atom and are optionally substituted asspecified with respect to R¹. In one embodiment, optional substituentsR¹¹ on a cycloalkenyl group representing R¹ are chosen from fluorine and(C₁-C₄)-alkyl. In one embodiment, cycloalkenyl groups contain one doublebond within the ring which can be present in any position. Examples ofcycloalkenyl are cyclopentenyl including cyclopent-1-enyl,cyclopent-2-enyl and cyclopent-3-enyl, cyclohexenyl includingcyclohex-1-enyl, cyclohex-2-enyl and cyclohex-3-enyl, and cycloheptenylincluding cyclohept-1-enyl, cyclohept-2-enyl, cyclopent-3-enyl andcyclohept-4-enyl. Examples of residues of rings, from any one or more ofwhich R¹ is chosen in one embodiment of the invention, are cyclobutyl,cyclopentyl, cyclohexyl, phenyl, oxetanyl including oxetan-3-yl,tetrahydrofuranyl including tetrahydrofuran-3-yl, tetrahydrothiophenylincluding tetrahydrothiophen-3-yl, tetrahydropyranyl includingtetrahydropyran-4-yl, azetidinyl including azetidin-1-yl, pyrrolidinyl,piperidinyl, imidazolidinyl, piperazinyl, morpholinyl includingMorpholin-1-yl, thiomorpholinyl, furanyl including furan-3-yl,thiophenyl including thiophen-3-yl, pyrazolyl including pyrazol-3-yl,imidazolyl, thiazolyl including thiazol-2-yl, pyridinyl includingpyridin-2-yl, pyridin-3-yl and pyridin-4-yl, pyridazinyl includingpyridazin-3-yl, wherein in all of them, if applicable, one or two of thering nitrogen atoms can carry a hydrogen atom or (C₁-C₄)-alkyl, andwherein all of them are optionally substituted on one or more ringcarbon atoms by identical or different substituents R¹¹, and wherein inall of them, if applicable, a ring sulfur atom can be non-oxidized, i.e.be present as a sulfur atom, or carry one or two oxo groups, i.e. bepresent in the form of a sulfoxide or sulfone.

In one embodiment, R¹ is chosen from phenyl and a residue of a saturatedor unsaturated 3-membered to 7-membered, monocyclic ring, in anotherembodiment from phenyl and a residue of a saturated or unsaturated5-membered to 7-membered, monocyclic ring, in another embodiment fromphenyl, pyridinyl and a residue of a saturated 3-membered to 7-membered,monocyclic ring, in another embodiment from phenyl, pyridinyl and aresidue of a saturated 5-membered to 7-membered, monocyclic ring, inanother embodiment from phenyl and a residue of a saturated 3-memberedto 7-membered, monocyclic ring, in another embodiment from phenyl and aresidue of a saturated 5-membered to 7-membered, monocyclic ring,wherein in all these embodiments the monocyclic ring comprises 1 or 2identical or different ring heteroatoms chosen from N, O and S, whereinone or two of the ring nitrogen atoms can carry a hydrogen atom or a(C₁-C₄)-alkyl substituent and one or two of the ring sulfur atoms cancarry one or two oxo groups, and wherein the phenyl, pyridinyl andresidue of a ring are optionally substituted on one or more ring carbonatoms by identical or different substituents R¹¹, and wherein pyridinylincludes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl. In anotherembodiment, R¹ is chosen from phenyl and pyridinyl, in anotherembodiment R¹ is pyridinyl, and in another embodiment R¹ is phenyl,wherein in these embodiments pyridinyl includes the groups pyridin-2-yl,pyridin-3-yl and pyridin-4-yl and in one embodiment is chosen from anyone or more of these groups, and wherein in all these embodiments thephenyl and the pyridinyl are optionally substituted on one or more ringcarbon atoms by identical or different substituents R¹¹.

In one embodiment of the invention, the number w is chosen from 0 and 1,in another embodiment it is 0, in another embodiment it is 1. In oneembodiment, a (C₃-C₇)-cycloalkyl group present in R²¹ is(C₃-C₆)-cycloalkyl, in another embodiment (C₃-C₅)-cycloalkyl, in anotherembodiment cyclopropyl. In one embodiment, R²¹ is chosen from(C₁-C₄)-alkyl and oxy, in another embodiment R²¹ is (C₁-C₄)-alkyl, inanother embodiment it is (C₁-C₃)-alkyl, in another embodiment it ismethyl, and in another embodiment it is oxy.

In one embodiment of the invention, the number of ring heteroatoms in anaromatic heterocycle representing R² is 1 or 2, in another embodiment itis 1. In one embodiment of the invention, R² is chosen from phenyl and aresidue of an aromatic, 6-membered monocyclic heterocycle whichcomprises 1, 2 or 3 ring nitrogen atoms, in another embodiment 1 or 2ring nitrogen atoms, in another embodiment 1 ring nitrogen atom, whereinone of the ring nitrogen atoms can carry a substituent R²¹ which is oxy,i.e. wherein one of the ring nitrogen atoms can be oxidized to theN-oxide, and wherein the phenyl and residue of an aromatic heterocycleare optionally substituted on one or more ring carbon atoms by identicalor different substituents R²². In another embodiment, R² is phenyl,wherein the phenyl is optionally substituted on one or more ring atomsby identical or different substituents R²², and in another embodiment R²is pyridinyl, wherein the ring nitrogen atom can carry a substituent R²¹which is oxy, i.e. wherein the ring nitrogen atom can be oxidized to theN-oxide, and wherein the pyridinyl is optionally substituted on one ormore ring carbon atoms by identical or different substituents R²². Inanother embodiment, R² is a residue of an aromatic 5-memberedheterocycle which comprises 1, 2 or 3 identical or different ringheteroatoms chosen from N, O and S, wherein one of the ring nitrogenatoms can carry a hydrogen atom or a substituent R²¹, and wherein theresidue of an aromatic heterocycle is optionally substituted on one ormore ring carbon atoms by identical or different substituents R²². Inone embodiment, a residue of an aromatic heterocyclic group representingR² is chosen from furanyl, thiophenyl, oxazolyl, thiazolyl, pyridinyl,pyridazinyl, pyrimidinyl and pyrazinyl, in another embodiment fromfuranyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl andpyrazinyl, in another embodiment from furanyl, thiophenyl, pyridinyl,pyridazinyl, pyrimidinyl and pyrazinyl, in another embodiment fromfuranyl, thiophenyl, pyridinyl and pyrimidinyl, in another embodimentfrom furanyl, thiophenyl and pyridinyl, which are all optionallysubstituted as indicated with respect to R². In another embodiment, R²is chosen from one or more of the groups furan-2-yl, thiophen-2-yl,pyridin-3-yl, pyridin-4-yl and pyrimidin-5-yl, in another embodimentfrom phenyl, furan-2-yl, thiophen-2-yl, pyridin-3-yl, pyridin-4-yl andpyrimidin-5-yl, in another embodiment from pyridin-3-yl andpyridin-4-yl, in another embodiment from phenyl, pyridin-3-yl andpyridin-4-yl, which all are optionally substituted as indicated withrespect to R². In one embodiment, the number of substituents R²² whichare optionally present on ring carbon atoms in R², is 1, 2, 3, 4 or 5,in another embodiment 1, 2, 3 or 4, in another embodiment 1, 2 or 3, inanother embodiment 1 or 2, in another embodiment 1. Ring carbon atoms inR² which do not carry a substituent R²², carry a hydrogen atom.

In one embodiment of the invention, R¹¹ is chosen from halogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, hydroxy, (C₁-C₄)-alkyloxy, oxo,(C₁-C₄)-alkyl-S(O)_(m)—, amino, (C₁-C₄)-alkylamino,di((C₁-C₄)-alkyl)amino, (C₁-C₄)-alkylcarbonylamino,(C₁-C₄)-alkylsulfonylamino, cyano, (C₁-C₄)-alkylcarbonyl, aminosulfonyl,(C₁-C₄)-alkylaminosulfonyl and di((C₁-C₄)-alkyl)aminosulfonyl, inanother embodiment from halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,hydroxy, (C₁-C₄)-alkyloxy, oxo, (C₁-C₄)-alkyl-S(O)_(m)-, amino,(C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, cyano, aminosulfonyl,(C₁-C₄)-alkylaminosulfonyl and di((C₁-C₄)-alkyl)aminosulfonyl, inanother embodiment from halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,hydroxy, (C₁-C₄)-alkyloxy, oxo, (C₁-C₄)-alkyl-S(O)_(m)—, amino,(C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, cyano and aminosulfonyl, inanother embodiment from halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,hydroxy, (C₁-C₄)-alkyloxy, oxo, amino, (C₁-C₄)-alkylamino,di((C₁-C₄)-alkyl)amino, cyano and aminosulfonyl, in another embodimentfrom halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, hydroxy,(C₁-C₄)-alkyloxy, oxo, amino, (C₁-C₄)-alkylamino anddi((C₁-C₄)-alkyl)amino, in another embodiment from halogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, (C₁-C₄)-alkyloxy anddi((C₁-C₄)-alkyl)amino, in another embodiment from halogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, hydroxy and (C₁-C₄)-alkyloxy, inanother embodiment from halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyloxy, inanother embodiment from fluorine, chlorine, (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl, hydroxy and (C₁-C₄)-alkyloxy, wherein in all theseembodiments all alkyl groups independently of each other are optionallysubstituted by one or more fluorine substituents.

In one embodiment, the optional substituents R¹¹ on the residue of anaromatic ring representing R¹, for example on a phenyl group orpyridinyl group representing R¹, are chosen from halogen, (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl, hydroxy, (C₁-C₄)-alkyloxy, (C₁-C₄)-alkyl-S(O)_(m)—,amino, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino,(C₁-C₄)-alkylcarbonylamino, (C₁-C₄)-alkylsulfonylamino, cyano,(C₁-C₄)-alkylcarbonyl, aminosulfonyl, (C₁-C₄)-alkylaminosulfonyl anddi((C₁-C₄)-alkyl)aminosulfonyl, in another embodiment from halogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, hydroxy, (C₁-C₄)-alkyloxy,(C₁-C₄)-alkyl-S(O)_(m)—, amino, (C₁-C₄)-alkylamino,di((C₁-C₄)-alkyl)amino, cyano, anninosulfonyl,(C₁-C₄)-alkylaminosulfonyl and di((C₁-C₄)-alkyl)aminosulfonyl, inanother embodiment from halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,hydroxy, (C₁-C₄)-alkyloxy, (C₁-C₄)-alkyl-S(O)_(m)—, amino,(C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, cyano and aminosulfonyl, inanother embodiment from halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,hydroxy, (C₁-C₄)-alkyloxy, amino, (C₁-C₄)-alkylamino,di((C₁-C₄)-alkyl)amino, cyano and aminosulfonyl, in another embodimentfrom halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, hydroxy,(C₁-C₄)-alkyloxy, amino, (C₁-C₄)-alkylamino and di((C₁-C₄)-alkyl)amino,in another embodiment from halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₁-C₄)-alkyloxy and di((C₁-C₄)-alkyl)amino, in another embodiment fromhalogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, hydroxy and(C₁-C₄)-alkyloxy, in another embodiment from halogen, (C₁-C₄)-alkyl and(C₁-C₄)-alkyloxy, in another embodiment from fluorine, chlorine,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, hydroxy and (C₁-C₄)-alkyloxy, whereinin all these embodiments all alkyl groups independently of each otherare optionally substituted by one or more fluorine substituents.

In one embodiment, the optional substituents R¹¹ on the residue of asaturated or non-aromatic unsaturated ring representing R¹ are chosenfrom halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, hydroxy,(C₁-C₄)-alkyloxy, oxo, (C₁-C₄)-alkyl-S(O)_(m)—, amino,(C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, (C₁-C₄)-alkylcarbonylamino,(C₁-C₄-alkylsulfonylamino and cyano, in another embodiment from halogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, hydroxy, (C₁-C₄)-alkyloxy, oxo,amino, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino and cyano, in anotherembodiment from halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, hydroxy,(C₁-C₄)-alkyloxy and oxo, in another embodiment from halogen,(C₁-C₄)-alkyl, hydroxy, (C₁-C₄)-alkyloxy and oxo, in another embodimentfrom fluorine, chlorine, (C₁-C₄)-alkyl, hydroxy, (C₁-C₄)-alkyloxy andoxo, in another embodiment from (C₁-C₄)-alkyl, hydroxy and oxo, inanother embodiment from alkyl and hydroxy, and in another embodimentthey are (C₁-C₄)-alkyl, wherein in all these embodiments all alkylgroups independently of each other are optionally substituted by one ormore fluorine substituents. In case the residue of a ring representingR¹ contains any oxo groups as substituents R¹¹, in one embodiment notmore than two such oxo substituents are present, and in anotherembodiment not more than one such oxo substituent is present.

In one embodiment of the invention, the substituents R²² which areoptionally present on the group R², are chosen from halogen, hydroxy,(C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy-, (C₁-C₄)-alkyl-S(O)_(m)—, amino,nitro, cyano, R²³ and R²³—O—, in another embodiment from halogen,hydroxy, (C₁-C₄)-alkyloxy-, amino, cyano, R²³ and R²³—O—, in anotherembodiment from halogen, hydroxy, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy-, R²³and R²³—O—, in another embodiment from halogen, hydroxy, (C₁-C₄)-alkyl-and (C₁-C₄)-alkyloxy-, wherein in all these embodiments R²³ is asdefined.

In one embodiment, 1, 2 or 3 of the substituents R²², in anotherembodiment 1 or 2 of the substituents R²², and in another embodiment 1of the substituents R²², which are optionally present on the group R²,are defined as in the general definition of R²² and thus are chosen fromhalogen, hydroxy, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy-, alkyl-S(O)_(m)—,amino, nitro, cyano, hydroxycarbonyl, (C₁-C₄)-alkyloxycarbonyl,aminocarbonyl, aminosulfonyl, R²³ and R²³—O—, wherein R²³ is as defined,and any further substituents R²² which are optionally present on thegroup R², for example 1, 2 or 3 further substituents R²², or 1 or 2further substituents R²², or 1 further substituent R²², are chosen fromhalogen, hydroxy, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy-,(C₁-C₄)-alkyl-S(O)_(m)—, amino, nitro, cyano, R²³ and R²³—O—, whereinall alkyl groups independently of each other are optionally substitutedby one or more fluorine substituents as generally applies to alkylgroups. In one embodiment, the said substituents R²² which areoptionally present on the group R² and which in the afore-mentionedembodiment are defined as in the general definition of R²², for example1 or 2 such substituents R²², or 1 such substituent R²², are chosen fromhalogen, hydroxy, (C₁-C₄)-alkyloxy-, (C₁-C₄)-alkyl-S(O)_(m)—, amino,nitro, cyano, R²³ and R²³—O—, in another embodiment from halogen,hydroxy, (C₁-C₄)-alkyl-S(O)_(m)—, amino, R²³ and R²³—O—, in anotherembodiment from halogen, hydroxy, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy-,amino, R²³ and R²³—O—, in another embodiment from halogen, hydroxy,(C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy-, (C₁-C₄)-alkyl-S(O)_(m)-, amino andcyano, in another embodiment from halogen, hydroxy, (C₁-C₄)-alkyl-,(C₁-C₄)-alkyloxy- and cyano, wherein R²³ is as defined. In oneembodiment, the said substituents R²² which are optionally present onthe group R² and which in the afore-mentioned embodiment are defined asin the general definition of R²², for example 1 or 2 such substituentsR²², or 1 such substituent R²², are not located on ring carbon atomswithin the group R² which are adjacent to the atom via which the groupR² is bonded to the oxazolopyrimidine ring depicted in formula I. Inanother embodiment, in the case of a phenyl group representing R², 1 or2 such substituents R²², or 1 such substituent R²², is optionallypresent in any of positions 3, 4 and 5 of the phenyl group, and inanother embodiment 1 such substituent R²² is present in position 4 ofthe phenyl group. In one embodiment, the said further substituents R²²which are optionally present on the group R², for example 1, 2 or 3further substituents R²², or 1 or 2 further substituents R²², or 1further substituent R²², are chosen from halogen, hydroxy,(C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy-, (C₁-C₄)-alkyl-S(O)_(m)—, amino andcyano, in another embodiment from halogen, hydroxy, (C₁-C₄)-alkyl-,(C₁-C₄)-alkyloxy-, amino and cyano, in another embodiment from halogen,hydroxy, (C₁-C₄)-alkyloxy- and cyano, in another embodiment fromhalogen, (C₁-C₄)-alkyl- and (C₁-C₄)-alkyloxy-, in another embodimentfrom halogen and (C₁-C₄)-alkyl-, wherein in all these embodiments allalkyl groups independently of each other are optionally substituted byone or more fluorine substituents.

In one embodiment of the invention, R²³ is a residue of a monocyclicring, in another embodiment a residue of a bicyclic ring. The residue ofa ring representing R²³ can be carbocyclic or heterocyclic. In oneembodiment, the residue of a monocyclic ring representing R²³ iscarbocyclic, in another embodiment heterocyclic. In one embodiment, theresidue of a bicyclic ring representing R²³ is carbocyclic, in anotherembodiment heterocyclic. In one embodiment of the invention, the numberof ring heteroatoms in R²³ is 0, 1, 2 or 3, in another embodiment 0, 1or 2, in another embodiment 0 or 1, in another embodiment 1, 2, 3 or 4,in another embodiment 1, 2 or 3, in another embodiment 1 or 2, inanother embodiment 1, and in another embodiment it is 0, and in thislatter embodiment R²³ thus is a (C₃-C₇)-cycloalkyl group. In oneembodiment, the residue of a monocyclic ring representing R²³ is anoxetanyl group, for example oxetan-3-yl.

In one embodiment, the ring heteroatoms in R²³ are chosen from N and O,in another embodiment from O and S, in another embodiment they are N,and in another embodiment they are O, wherein ring nitrogen atoms cancarry a hydrogen atom or a (C₁-C₄)-alkyl substituent. R²³ can be bondedvia any suitable ring carbon atom and ring nitrogen atom. In case R²³ isbonded to an oxygen atom, in one embodiment R²³ is bonded via a ringcarbon atom. In another embodiment, R²³ is bonded via a ring carbon atomirrespective of the atom to which R²³ is bonded. In another embodiment,R²³ is bonded via a ring nitrogen atom. In one embodiment, the number ofoptional substituents R²⁴ on ring carbon atoms in R²³ is 1, 2, 3 or 4 or5, in another embodiment 1, 2, 3 or 4, in another embodiment 1, 2 or 3,in another embodiment 1 or 2, in another embodiment 1. R²³ can be3-membered, 4-membered, 5-membered, 6-membered or 7-membered. In oneembodiment, R²³ is 4-membered to 7-membered, in another embodiment4-membered to 6-membered, in another embodiment 5-membered to6-membered, in another embodiment 4-membered to 5-membered. In oneembodiment, a 3-membered ring representing R²³ does not comprise anyring heteroatoms. Examples of residues of rings from any one or more ofwhich R²³ is chosen in one embodiment of the invention, are oxetan-3-yl,azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl,morpholin-4-yl and piperazin-1-yl, which are all optionally substitutedas indicated. In one embodiment, R²³ is chosen from any one or more ofthe residues oxetan-3-yl, pyrrolidin-1-yl, piperidin-1-yl,morpholin-4-yl and piperazin-1-yl, in another embodiment from any one ormore of the residues oxetan-3-yl, azetidin-1-yl, morpholin-4-yl andpiperazin-1-yl, in another embodiment from any one or more of theresidues oxetan-3-yl, azetidin-1-yl, pyrrolidin-1-yl, andpiperidin-1-yl, and in another embodiment R²³ is oxetan-3-yl, which areall optionally substituted as indicated.

In one embodiment of the invention, R²⁴ is chosen from halogen,(C₁-C₄)-alkyl, and hydroxy, in another embodiment from fluorine,(C₁-C₄)-alkyl and hydroxy, in another embodiment from fluorine, methyland hydroxy, in another embodiment from fluorine and methyl, in anotherembodiment from methyl and hydroxy, in another embodiment from fluorine,(C₁-C₄)-alkyl, hydroxy and oxo.

In one embodiment of the invention, the ring heteroatoms in Het arechosen from N and O, in another embodiment from O and S, in anotherembodiment they are O atoms. In another embodiment, the number of ringheteroatoms in Het is 1. In one embodiment, two ring oxygen atoms in Hetare not present in adjacent ring positions, in another embodiment tworing heteroatoms chosen from O and S are not present in adjacent ringpositions, in another embodiment two ring heteroatoms are not present inadjacent ring positions. Ring nitrogen atoms in Het carry a hydrogenatom or a substituent as specified. In one embodiment, optionalsubstituents on ring nitrogen atoms in Het are (C₁-C₄)-alkylsubstituents. In one embodiment, optional substituents on ring nitrogenatoms and ring carbon atoms in Het are (C₁-C₄)-alkyl substituents. Inone embodiment, the number of optional substituents on Het is 1, 2, 3, 4or 5, in another embodiment 1, 2, 3 or 4, in another embodiment 1, 2 or3, in another embodiment 1 or 2, in another embodiment 1. Het can bebonded via any suitable ring carbon atom. In one embodiment, Het isbonded via a ring carbon atom which is not adjacent to a ringheteroatom. Het can be 4-membered, 5-membered, 6-membered or 7-membered.In one embodiment, Het is 4-membered or 5-membered, in anotherembodiment 5-membered to 7-membered, in another embodiment 5-membered or6-membered, in another embodiment 4-membered. Examples of Het, from anyone or more of which Het is chosen in one embodiment, are oxetanylincluding oxetan-2-yl and oxetan-3-yl, tetrahydrofuranyl includingtetrahydrofuran-2-yl and tetrahydrofuran-3-yl, tetrahydropyranylincluding tetrahydropyran-2-yl, tetrahydropyran-3-yl andtetrahydropyran-4-yl, oxepanyl including oxepan-2-yl, oxepan-3-yl andoxepan-4-yl, [1,3]dioxolanyl including [1,3]dioxolan-2-yl and[1,3]dioxolan-4-yl, [1,4]dioxanyl including [1,4]dioxan-2-yl, thietanylincluding thietan-2-yl and thietan-3-yl, tetrahydrothiophenyl includingtetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl,tetrahydrothiopyranyl including tetrahydrothiopyran-2-yl,tetrahydrothiopyran-3-yl and tetrahydrothiopyran-4-yl, [1,4]dithianylincluding [1,4]dithian-2-yl, azetidinyl including azetidin-2-yl andazetidin-3-yl, pyrrolidinyl including pyrrolidinyl-2-yl andpyrrolidinyl-3-yl, piperidinyl including piperidinyl-2-yl,piperidinyl-3-yl and piperidinyl-4-yl, azepanyl including azepan-2-yl,azepan-3-yl and azepan-4-yl, oxazolidinyl including oxazolidin-2-yl,oxazolidin-4-yl and oxazolidin-5-yl, thiazolidinyl includingthiazolidin-2-yl, thiazolidin-4-yl and thiazolidin-5-yl, morpholinylincluding morpholin-2-yl and morpholin-3-yl, thiomorpholinyl includingthiomorpholin-2-yl and thiomorpholin-3-yl, which all are optionallysubstituted as specified with respect to Het.

A subject of the invention are all compounds of the formula I whereinany one or more structural elements such as groups, substituents andnumbers are defined as in any of the specified embodiments ordefinitions of the elements or have any one or more of the specificmeanings which are mentioned herein as examples of elements, wherein allcombinations of one or more specified embodiments and/or definitionsand/or specific meanings of the elements are a subject of the presentinvention. Also with respect to all such compounds of the formula I, alltheir stereoisomeric forms and mixtures of stereoisomeric forms in anyratio, and their physiologically acceptable salts, and thephysiologically acceptable solvates of any of them, are a subject of thepresent invention.

An example of compounds of the invention which with respect to anystructural elements are defined as in specified embodiments of theinvention or definitions of such elements, and which are a subject ofthe invention, are compounds of the formula I, wherein

A is chosen from 0 and S;

R¹ is chosen from (C₃-C₇)-cycloalkyl-C_(u)H_(2u)— and Het-C_(v)H_(2v)—,wherein u and v are chosen from 1 and 2, or R¹ is a residue of asaturated or unsaturated, 3-membered to 10-membered, monocyclic orbicyclic ring which comprises 0, 1, 2, 3 or 4 identical or differentring heteroatoms chosen from N, O and S, wherein one or two of the ringnitrogen atoms can carry a hydrogen atom or a (C₁-C₄)-alkyl substituentand one or two of the ring sulfur atoms can carry one or two oxo groups,and wherein the residue of a ring is optionally substituted on one ormore ring carbon atoms by identical or different substituents R¹¹;

R² is chosen from phenyl and pyridinyl, wherein the ring nitrogen atomof the pyridinyl can carry an oxy substituent, and wherein the phenyland the pyridinyl are optionally substituted on one or more ring carbonatoms by identical or different substituents R²²;

and all other groups and numbers are defined as in the generaldefinition of the compounds of the formula I or in any specifiedembodiments of the invention or definitions of structural elements, inany of their stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, and their physiologically acceptable salts, and thephysiologically acceptable solvates of any of them.

Another such example are compounds of the formula I, wherein

A is O;

R¹ is chosen from (C₃-C₇)-cycloalkyl-C_(u)H_(2u)— and Het-C_(v)H_(2v)—,wherein u and v are chosen from 1 and 2, or R¹ is a residue of asaturated or unsaturated, 3-membered to 7-membered, monocyclic ringwhich comprises 0, 1 or 2 identical or different ring heteroatoms chosenfrom N, O and S, wherein one or two of the ring nitrogen atoms can carrya hydrogen atom or a (C₁-C₄)-alkyl substituent and one or two of thering sulfur atoms can carry one or two oxo groups, and wherein theresidue of a ring is optionally substituted on one or more ring carbonatoms by identical or different substituents R¹¹;

R² is chosen from phenyl and pyridinyl, wherein the ring nitrogen atomof the pyridinyl can carry an oxy substituent, and wherein the phenyland the pyridinyl are optionally substituted on one or more ring carbonatoms by identical or different substituents R²²;

R¹¹ is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy and cyano;

R²² is chosen from halogen, hydroxy, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy,cyano, R²³ and R²³—O—;

R²³ is a residue of a saturated 3-membered to 6-membered, monocyclicring which comprises 0 or 1 ring heteroatom chosen from N, O and S,wherein one or two of the ring nitrogen atoms can carry a hydrogen atomor a (C₁-C₄)-alkyl substituent and one of the ring sulfur atoms cancarry one or two oxo groups, and wherein the residue of a ring isoptionally substituted on one or more ring carbon atoms by identical ordifferent substituents R²⁴;

R²⁴ is chosen from fluorine, (C₁-C₄)-alkyl and hydroxy;

Het is a residue of a saturated, 4-membered to 7-membered, monocyclicheterocycle which comprises 1 ring heteroatom chosen from N, O and S andwhich is bonded via a ring carbon atom, wherein the residue of aheterocycle is optionally substituted by one or more identical ordifferent substituents chosen from fluorine and (C₁-C₄)-alkyl;

wherein all cycloalkyl groups, independently of each other andindependently of any other substituents, are optionally substituted byone or more identical or different substituents chosen from fluorine and(C₁-C₄)-alkyl;

wherein all alkyl, C_(u)H_(2u) and C_(v)H_(2v), groups, independently ofeach other and independently of any other substituents, are optionallysubstituted by one or more fluorine substituents,

in any of their stereoisomeric forms or a mixture of stereoisomericforms in any ratio, and their physiologically acceptable salts, and thephysiologically acceptable solvates of any of them.

Another such example are compounds of the formula I, wherein

A is O;

R¹ is is a residue of a saturated or unsaturated, 3-membered to7-membered, monocyclic ring which comprises 0 or 1 ring heteroatomschosen from N, O and S, wherein a ring nitrogen atom can carry ahydrogen atom or a (C₁-C₄)-alkyl substituent and a ring sulfur atom cancarry one or two oxo groups, and wherein the residue of a ring isoptionally substituted on one or more ring carbon atoms by identical ordifferent substituents R¹¹;

R² is chosen from phenyl and pyridinyl, wherein the ring nitrogen atomof the pyridinyl can carry an oxy substituent, and wherein the phenyland the pyridinyl are optionally substituted on one or more ring carbonatoms by identical or different substituents R²²;

R¹¹ is chosen from halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyloxy;

R²² is chosen from halogen, hydroxy, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy,R²³ and R²³—O—;

R²³ is a residue of a saturated 3-membered to 6-membered, monocyclicring which comprises 0 or 1 ring heteroatom chosen from N, O and S,wherein one or two of the ring nitrogen atoms can carry a hydrogen atomor a (C₁-C₄)-alkyl substituent and one of the ring sulfur atoms cancarry one or two oxo groups, and wherein the residue of a ring isoptionally substituted on one or more ring carbon atoms by identical ordifferent substituents R²⁴;

R²⁴ is chosen from fluorine, (C₁-C₄)-alkyl and hydroxy;

wherein all cycloalkyl groups, independently of each other andindependently of any other substituents, are optionally substituted byone or more identical or different substituents chosen from fluorine and(C₁-C₄)-alkyl;

wherein all alkyl groups, independently of each other and independentlyof any other substituents, are optionally substituted by one or morefluorine substituents, in any of their stereoisomeric forms or a mixtureof stereoisomeric forms in any ratio, and their physiologicallyacceptable salts, and the physiologically acceptable solvates of any ofthem.

Likewise, also with respect to all specific compounds disclosed herein,such as the example compounds which represent embodiments of theinvention wherein the various groups and numbers in the generaldefinition of the compounds of the formula I have the specific meaningspresent in the respective specific compound, it applies that they are asubject of the present invention in any of their stereoisomeric formsand or a mixture of stereoisomeric forms in any ratio, and in the formof their physiologically acceptable salts, and in the form of thephysiologically acceptable solvates of any of them. Irrespective thereofwhether a specific compound is disclosed herein as a free compoundand/or as a specific salt, it is a subject of the invention both in theform of the free compound and in the form of all its physiologicallyacceptable salts, and if a specific salt is disclosed, additionally inthe form of this specific salt, and in the form of the physiologicallyacceptable solvates of any of them. Thus, a subject of the inventionalso is a compound of the formula I which is chosen from any one or moreof the specific compounds of the formula I disclosed herein, includingthe example compounds specified below, and the physiologicallyacceptable salts thereof, and the physiologically acceptable solvates ofany of them, wherein the compound of the formula I is a subject of theinvention in any of its stereoisomeric forms or as a mixture ofstereoisomeric forms in any ratio, if applicable. As an examplementioned is a compound of the formula I, or a physiologicallyacceptable salt thereof, or a physiologically acceptable solvate of anyof them, which is chosen from

-   5-(2-fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4-d]pyrimidine,-   4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol,-   5-(2-fluoro-phenoxy)-2-(3-methoxy-phenyl)-oxazolo[5,4-d]pyrimidine,-   4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-phenol,-   5-(2-fluoro-phenoxy)-2-(4-methoxy-3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine,-   5-(2-fluoro-phenoxy)-2-(4-methoxy-3-trifluoromethyl-phenyl)-oxazolo[5,4-d]pyrimidine,-   4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2-methyl-phenol,-   2-(4-methoxy-3,5-dimethyl-phenyl)-5-phenoxy-oxazolo[5,4-d]pyrimidine,-   2-(4-methoxy-3,5-dimethyl-phenyl)-5-(pyridin-3-yloxy)-oxazolo[5,4-d]pyrimidine,    and-   4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2-trifluoromethyl-phenol.

Another subject of the present invention are processes for thepreparation of the compounds of the formula I and their salts andsolvates, by which the compounds are obtainable and which are outlinedin the following. In one process, a compound of the formula II isreacted with a compound of the formula Ill to give a compound of theformula I,

wherein the groups A, R¹ and R² in the compounds of the formulae II andIII are defined as in the compounds of the formula I and additionallyfunctional groups can be present in protected form or in the form of aprecursor group which is later converted into the final group. The groupL¹ in the compounds of the formula II is a leaving group which can bereplaced in a nucleophilic aromatic substitution reaction, such as asulfonyloxy group, for example methanesulfonyloxy ortrifluoromethanesulfonyloxy, a halogen atom, for example chlorine orbromine, or a sulfoxide group or a sulfone group, for example a group ofthe formula —S(O)-Alk or —S(O)₂-Alk wherein Alk is a (C₁-C₄)-alkylgroup, for example methyl or ethyl.

The reaction of the compounds of the formulae II and III is anucleophilic aromatic substitution reaction at the carbon atom in the5-position of oxazolo[5,4-d]pyrimidine ring, i.e. in the pyrimidinemoiety, and can be carried out under standard conditions for suchreactions which are well known to a person skilled in the art. Generallythe reaction is carried out in an inert solvent, for example ahydrocarbon or chlorinated hydrocarbon such as benzene, toluene, xylene,chlorobenzene, dichloromethane, chloroform or dichloroethane, an ethersuch as tetrahydrofuran (THF), dioxane, dibutyl ether, diisopropyl etheror 1,2-dimethoxyethane (DME), a ketone such as acetone or butan-2-one,an ester such as ethyl acetate or butyl acetate, a nitrile such asacetonitrile, an amide such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA) or N-methylpyrrolidin-2-one (NMP), or amixture of solvents, at temperatures from about 20° C. to about 160° C.,for example at temperatures from about 40° C. to about 100° C.,depending on the particulars of the specific case. Generally it isfavorable for enhancing the nucleophilicity of the compound of theformula III to add a base, for example a tertiary amine, such astriethylamine, ethyldiisopropylamine or N-methylmorpholine, or aninorganic base such as an alkaline earth metal hydride, hydroxide,carbonate or hydrogencarbonate like sodium hydride, sodium hydroxide,potassium hydroxide, sodium carbonate, potassium carbonate, cesiumcarbonate or sodium hydrogencarbonate, or an alkoxide or amide such assodium methoxide, sodium ethoxide, potassium methoxide, potassiumtert-butoxide, sodium amide or lithium diisopropylamide. A compound ofthe formula III can also be treated with a base and converted into asalt separately before the reaction with the compound of the formula II.

The starting compounds of the formulae II and III can be obtained byprocedures described in the literature or analogously to proceduresdescribed in the literature, and in many cases are commerciallyavailable. For example, the compounds of the formula II can be obtainedby reacting a 5-amino-pyrimidine derivative of the formula IV with anactivated carboxylic acid derivative of the formula V to give a compoundof the formula VI, cyclizing the latter compound with formation of theoxazolo[5,4-d]pyrimidine ring system to give a compound of the formulaVII which can already be a compound of the formula II depending on themeaning of R′ and L¹, and optionally modifying the group R′ in thecompound of the formula VII to give a compound of the formula II.

The group R² in the compounds of the formulae V, VI and VII is definedas in the compounds of the formula I and additionally functional groupscan be present in protected form or in the form of a precursor groupwhich is later converted into the final group. The groups R′ in thecompounds of the formulae IV, VI and VII can be a hydroxy group or ahalogen atom, such as chlorine or bromine. The group L² in the compoundsof the formula V is a nucleophilically substitutable leaving group andcan in particular be a halogen atom, such as chlorine or bromine, andthe compound of the formula V can thus be a carboxylic acid halide. L²can also be a group of the formula R²—C(O)—O and the compound of theformula V can thus be a carboxylic acid anhydride, for example.Compounds occurring in the synthesis of the compounds of the formula I,such as the compound of the formula IV, may also be present in anothertautomeric form, for example in the keto form in case the groups R′ inthe compound of the formula IV are hydroxy groups. Compounds occurringin the synthesis of the compounds of the formula I, including startingcompounds, intermediates and products, can also be employed or obtainedin the form of a salt.

The compounds of the formula IV are commercially available or can beobtained according to procedures described in the literature. Forexample, the compound of the formula IV in which R′ is hydroxy, which isthe compound 5-amino-uracil in its tautomeric hydroxy form, can beobtained from uracil by nitration to give 5-nitro-uracil, and reductionof the nitro group, for example as described in B. Johnson et al., J.Am. Chem. Soc. 41 (1919), 782-789. The compound of the formula IV inwhich R′ is chlorine, i.e. 5-amino-2,4-dichloro-pyrimidine, can beobtained from 5-nitro-uracil by chlorination, for example by treatmentwith phosphorus oxychloride, and reduction of the nitro group in theobtained 2,4-dichloro-5-nitro-pyrimidine, for example as described in N.Whittaker, J. Chem. Soc. (1951), 1565-1570.

The reaction of the compounds of the formulae IV and V can be carriedout under standard conditions for the acylation of an amine with anactivated carboxylic acid derivative like an acid halide or anhydride.Generally the reaction is carried out in an inert solvent, for example ahydrocarbon or chlorinated hydrocarbon such as benzene, toluene, xylene,chlorobenzene, dichloromethane, chloroform or dichloroethane, an ethersuch as THF, dioxane, dibutyl ether, diisopropyl ether or DME, a ketonesuch as acetone or butan-2-one, an ester such as ethyl acetate or butylacetate, or water, or a mixture of solvents, at temperatures from about−10° C. to about 40° C., for example at temperatures from about 0° C. toabout 30° C. Generally the reaction is carried out with addition of abase, for example a tertiary amine, such as triethylamine,ethyldiisopropylamine or N-methylmorpholine, or an inorganic base suchas an alkaline metal hydroxide, carbonate or hydrogencarbonate likesodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate or sodium hydrogencarbonate.

In case the group R′ in the compound of the formula VI is hydroxy, thecyclization of the compound of the formula VI to the compound of theformula VII can favorably be carried out in the presence of ahalogenating agent such as a phosphorus halide, like phosphoruspentachloride or phosphorus oxychloride or a mixture thereof, in aninert solvent, for example a hydrocarbon or chlorinated hydrocarbon suchas benzene, toluene, xylene, chlorobenzene, dichloromethane, chloroformor dichloroethane, at temperatures from about 20° C. to about 100° C.,for example temperatures from about 50° C. to about 80° C.

In case the group R′ in the compound of the formula VI is halogen suchas chlorine, the cyclization of the compound of the formula VI to thecompound of the formula VII can be carried out thermally, for example byheating the compound of the formula VI in an inert solvent such as ahydrocarbon or chlorinated hydrocarbon, for example toluene, xylene orchlorobenzene, or an amide, for example DMF, DMA or NMP, or a nitrile,for example acetonitrile, to temperatures from about 100° C. to about200° C., for example to temperatures from about 120° C. to about 180°C., optionally under pressure, and optionally in the presence of a base,such as a tertiary amine, for example triethylamine,ethyldiisopropylamine or N-methylmorpholine, or an inorganic base, forexample an alkaline metal hydroxide, carbonate or hydrogencarbonate likesodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate or sodium hydrogencarbonate. The thermal cyclization canfavorably be performed in a microwave reactor.

The compound of the formula VII can already be a compound of the formulaII and employed in the reaction with the compound of the formula III, ifit has been obtained from a compound of the formula VI in which R′ ishalogen, such as chlorine, and the halogen atom in the cyclizationproduct has not been replaced, for example during work-up, or if it hasbeen obtained from a compound of the formula VI in which R′ is hydroxy,and concomitantly with the cyclization the second hydroxy group in thecompound of the formula VII is halogenated, for example replaced with achlorine atom as may occur during the cyclization by means of aphosphorus halide. If a compound of the VII, in which R′ is hydroxy, isobtained as cyclization product, the hydroxy group can be converted intoa leaving group under standard conditions, for example into a halogenatom such as a chlorine atom by treatment with a halogenating agent suchas a phosphorus halide, or into a sulfonyloxy group as indicated aboveby treatment with a sulfonyl chloride or sulfonic acid anhydride.Depending on the particulars of the specific case, such as thereactivity of the specific compound of the formula III which is to bereacted with the compound of the formula II, it can also be advantageousto modify the group R′ in a compound of the formula VII even though italready is a leaving group. For example, a compound of the formula VIIin which R′ is halogen, such as chlorine, can be converted into acompound of the formula II in which L¹ is the group —S(O)₂-Alk and whichis then reacted with a compound of the formula Ill, by treatment with analkanesulfinic acid of the formula Alk-S(O)—OH, wherein Alk is(C₁-C₄)-alkyl. Such a conversion is generally carried out in thepresence of a base, such as an alkaline metal hydride, hydroxide,carbonate or hydrogencarbonate like sodium hydride, sodium hydroxide,potassium hydroxide, sodium carbonate, potassium carbonate, cesiumcarbonate or sodium hydrogencarbonate, in an inert solvent, such as ahydrocarbon or chlorinated hydrocarbon like benzene, toluene, xylene,chlorobenzene, dichloromethane, chloroform or dichloroethane, an ethersuch as THF, dioxane, dibutyl ether, diisopropyl ether or DME, an amidesuch as DMF or NMP, or a mixture of solvents, at temperatures from about20° C. to about 150° C., for example at temperatures from about 50° C.to about 120° C. An alkanesulfinic acid can also be treated with a baseand converted into a salt separately before the reaction with thecompound of the formula VII.

Further compounds of the formula I can be obtained from suitablecompounds prepared according to the above-described processes byfunctionalization or modification of contained functional groupsaccording to standard procedures, for example by esterification,amidation, hydrolysis, etherification, alkylation, acylation,sulfonylation, reduction, oxidation, conversion into salts, and others.For example, a hydroxy group, which may be liberated from an ether groupby ether cleavage, for example by means of boron tribromide, or from aprotected hydroxy group by deprotection, can be esterified to give acarboxylic acid ester or a sulfonic acid ester, or etherified.Etherifications of hydroxy groups can favorably be performed byalkylation with the respective halogen compound, for example a bromideor iodide, in the presence of a base, for example an alkaline metalcarbonate such potassium carbonate or cesium carbonate in an inertsolvent, for example an amide like DMF or NMP or a ketone like acetoneor butan-2-one, or with the respective alcohol under the conditions ofthe Mitsunobu reaction, i.e. in the presence of an azodicarboxylate suchas diethyl azodicarboxylate or diisopropyl azodicarboxylate and aphosphine such as triphenylphosphine or tributylphosphine in an inertaprotic solvent, for example an ether such as THF or dioxane (cf. O.Mitsunobu, Synthesis (1981), 1-28).

A hydroxy group can be converted into a halide by treatment with ahalogenating agent. A halogen atom can be replaced with a variety ofgroups in a substitution reaction which may also be a transition-metalcatalyzed reaction. A nitro group can be reduced to an amino group, forexample by catalytic hydrogenation. An amino group can be modified understandard conditions for alkylation, for example by reaction with ahalogen compound or by reductive amination of a carbonyl compound, orfor acylation or sulfonylation, for example by reaction with a reactivecarboxylic acid derivative, like an acid chloride or anhydride or asulfonic acid chloride, or with an activated carboxylic acid which maybe obtained from the carboxylic acid by treatment with a coupling agentlike N,N′-carbonyldiimidazole (CDI), a carbodiimide such as1,3-dicyclohexylcarbodiimide (DCC) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(cyano(ethoxycarbonyl)methyleneamino)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TOTU), or[(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammoniumtetrafluoroborate (TBTU), for example. A carboxylic ester group can behydrolyzed under acidic or basic conditions to give a carboxylic acid. Acarboxylic acid group can be activated or converted into a reactivederivative as mentioned afore and reacted with an alcohol or an amine orammonia to give an ester or amide. A primary amide can be dehydrated togive a nitrile. A sulfur atom, for example in an alkyl-S— group or in aheterocyclic ring, can be oxidized with a peroxide like hydrogenperoxide or a peracid to give a sulfoxide moiety S(O) or a sulfonemoiety S(O)₂. A carboxylic acid group, carboxylic acid ester group and aketone group can be reduced to an alcohol, for example by means of acomplex hydride such as lithium aluminium hydride, lithium borohydrideor sodium borohydride.

All reactions used in the above-described syntheses of the compounds ofthe formula I are per se well known to the skilled person and can becarried out under standard conditions according to, or analogously to,procedures described in the literature, for example in Houben-Weyl,Methoden der Organischen Chemie (Methods of Organic Chemistry),Thieme-Verlag, Stuttgart, or Organic Reactions, John Wiley & Sons, NewYork. If desired, the obtained compounds of the formula I, as well asany intermediate compounds, can be purified by customary purificationprocedures, for example by recrystallization or chromatography. Asalready mentioned, all starting compounds and intermediates employed inthe above-described syntheses which contain an acidic or basic group,can also be employed in the form of salts, and all intermediates andfinal target compounds can also be obtained in the form of salts. Aslikewise mentioned above, depending on the circumstances of the specificcase, in order to avoid an unwanted course of a reaction or sidereactions during the synthesis of a compound it can generally benecessary or advantageous to temporarily block functional groups byintroducing protective groups and deprotect them at a later stage of thesynthesis, or to introduce functional groups in the form of precursorgroups which later are converted into the desired functional groups. Asexamples of protecting groups amino-protecting groups may be mentionedwhich can be acyl groups or alkyloxycarbonyl groups, for example atert-butyloxycarbonyl group (=Boc) which can be removed by treatmentwith trifluoroacetic acid (=TFA), a benzyloxycarbonyl group which can beremoved by catalytic hydrogenation, or a fluoren-9-ylmethoxycarbonylgroup which can be removed by treatment with piperidine, and protectinggroups of carboxylic acid groups which can be protected as ester groups,such as tert-butyl esters which can be deprotected by treatment withtrifluoroacetic acid, or benzyl esters which can be deprotected bycatalytic hydrogenation. As an example of a precursor group the nitrogroup may be mentioned which can be converted into an amino group byreduction, for example by catalytic hydrogenation. Such synthesisstrategies, and protective groups and precursor groups which aresuitable in a specific case, are known to the skilled person.

Another subject of the present invention are the novel startingcompounds and intermediates occurring in the synthesis of the compoundsof the formula I, including the compounds of the formulae II, III, IV,V, VI and VII, wherein A, R¹, R², R′, L¹ and L² are defined as above, inany of their stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, and their salts, and solvates of any of them, and theiruse as intermediates. The invention also includes all tautomeric formsof the said intermediates and starting compounds. All explanations givenabove and embodiments specified above with respect to the compounds ofthe formula I also apply correspondingly to the said intermediates andstarting compounds. A subject of the invention are in particular thenovel specific starting compounds and intermediates disclosed herein.Independently thereof whether they are disclosed as a free compoundand/or as a specific salt, they are a subject of the invention both inthe form of the free compounds and in the form of their salts, and if aspecific salt is disclosed, additionally in the form of this specificsalt, and in the form of solvates of any of them.

The compounds of the formula I, optionally in combination with otherpharmacologically active compounds, can be administered to animals, inparticular to mammals including humans, as pharmaceuticals bythemselves, in mixtures with one another, or in the form ofpharmaceutical compositions. The administration can be carried outorally, for example in the form of tablets, film-coated tablets,sugar-coated tablets, granules, hard and soft gelatin capsules,solutions including aqueous, alcoholic and oily solutions, juices,drops, syrups, emulsions or suspensions, rectally, for example in theform of suppositories, or parenterally, for example in the form ofsolutions for subcutaneous, intramuscular or intravenous injection orinfusion, in particular aqueous solutions. The compounds of the formulaI can additionally be used in modes of local drug delivery, for examplein coated stents for preventing or reducing in-stent restenosis or byapplying them locally by means of a catheter. The appropriateadministration form depends, among others, on the disease to be treatedand on its severity.

The amount of a compound of the formula I and/or its physiologicallyacceptable salts and/or solvates present in the pharmaceuticalcompositions normally ranges from about 0.2 to about 800 mg, for examplefrom about 0.5 to about 500 mg, for example from about 1 to about 200mg, per unit dose, but depending on the type of the pharmaceuticalcomposition it may also be higher. The pharmaceutical compositionsusually comprise from about 0.5 to about 90 percent by weight of thecompound of the formula I and/or its physiologically acceptable saltsand/or solvates. The production of the pharmaceutical compositions canbe carried out in a manner known per se. To this end, one or morecompounds of the formula I and/or their physiologically acceptable saltsand/or solvates together with one or more solid or liquid pharmaceuticalcarrier substances, or vehicles, and/or additives, or auxiliarysubstances, and, if a combination medicament is desired, otherpharmacologically active compounds having therapeutic or prophylacticaction are brought into a suitable form for administration and dosagewhich can be used in human or veterinary medicine. As carrier substancesand additives, suitable organic and inorganic substances can be usedwhich do not react in an undesired manner with the compounds of theformula I or their physiologically acceptable salts or solvates. Asexamples of types of additives which can be contained in thepharmaceutical compositions and medicaments, lubricants, preservatives,thickeners, stabilizers, disintegrants, wetting agents, agents forachieving a depot effect, emulsifiers, salts, for example forinfluencing the osmotic pressure, buffer substances, colorants,flavorings and aromatic substances may be mentioned. Examples of carriersubstances and additives are water, physiological sodium chloridesolution, vegetable oils, waxes, alcohols such as ethanol, isopropanol;1,2-propanediol, benzyl alcohols or glycerol, polyols, mannitol,polyethylene glycols, polypropylene glycols, glycerol triacetate,polyvinylpyrrolidone, gelatin, cellulose, carbohydrates such as lactose,glucose, saccharose or starch like corn starch, stearic acid and itssalts such as magnesium stearate, talc, lanolin, petroleum jelly, ormixtures thereof, for example mixtures of water with one or more organicsolvents such as mixtures of water with alcohols. The compounds of theformula I and their physiologically acceptable salts and solvates canalso be lyophilized and the obtained lyophilisates used for theproduction of injectable compositions, for example.

The dosage of a compound of the formula I and/or a physiologicallyacceptable salt and/or solvate thereof to be administered depends on thespecific case and, as is usual, has to be adapted by the physicianaccording to the customary rules and procedures to the individualcircumstances in order to achieve an optimum effect. It depends, forexample, on the nature and the severity of the disorder to be treated,the sex, age, weight and individual responsiveness of the human oranimal patient, on the efficacy and duration of action of the compoundused, on whether the treatment is for the therapy of an acute or chronicdisease or prophylactic, or on whether other active compounds areadministered in addition to a compound of the formula I. In general, adaily dose from about 0.01 mg/kg to about 100 mg/kg, or from about 0.1mg/kg to about 10 mg/kg, or from about 0.3 mg/kg to about 5 mg/kg (ineach case mg per kg of bodyweight), for example, is appropriate foradministration to an adult weighing about 75 kg in order to obtain thedesired results. The daily dose can be administered in a single dose or,in particular when larger amounts are administered, divided intoseveral, for example two, three or four, individual doses. Theadministration can also be carried out continuously, for example bycontinuous infusion or injection. Depending on the individual behaviorin a specific case, it may be necessary to deviate upward or downwardfrom the indicated dosages.

The following examples illustrate the invention.

When example compounds containing a basic group were purified bypreparative high pressure liquid chromatography (HPLC) on reversed phase(RP) column material and, as customary, the eluent was a gradientmixture of water and acetonitrile containing trifluoroacetic acid (TFA),they were in part obtained in the form of their acid addition salt withtrifluoroacetic acid, depending on the details of the workup such asevaporation or lyophilization conditions. In the names of the examplecompounds and their structural formulae any such containedtrifluoroacetic acid is not specified.

The prepared compounds were in general characterized by spectroscopicdata and chromatographic data, in particular mass spectra (MS) and HPLCretention times (Rt; in min) which were obtained by combined analyticalHPLC/MS characterization (LC/MS), and/or nuclear magnetic resonance(NMR) spectra. In the NMR characterization, the chemical shift 6 (inppm), the number of hydrogen atoms and the multiplicity (s=singlet,d=doublet, dd=double doublet, t=triplet, dt=double triplet, q=quartet,m=multiplet; br=broad) of the signals is given. In the MScharacterization, in general the mass number (m/z) of the peak of themolecular ion M, e.g. M⁺, or of a related ion such as the ion M+1, e.g.[M+1]⁺, i.e. the protonated molecular ion [M+H]⁺, which was formeddepending on the ionization method used, is given. Generally, theionization method was electrospray ionization (ESI). The LC/MSconditions used were as follows.

Method LC1

Column: UPLC BEH C18, 50×2.1 mm, 1.7 μm; flow: 0.9 ml/min; eluent A:acetonitrile+0.08% formic acid; eluent B: water+0.1% formic acid;gradient: from 5% A+95% B to 95% A+5% B in 1.1 min, then 95% A+5% B for0.6 min; MS ionization method: ESI⁺

Method LC2

Column: YMC-Pack J′sphere H80, 33×2.1 mm, 4 μm, flow: 1.0 ml/min; eluentA: acetonitrile+0.05% TFA; eluent B: water+0.05% TFA; gradient: from 2%A+98% B to 95% A+5% B in 5 min, then 95% A+5% B for 1.25 min; MSionization method: ESI⁺

Method LC3

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; flow: 1.3 ml/min; eluentA: acetonitrile+0.05% TFA; eluent B: water+0.05% TFA; gradient: 5% A+95%B for 0.3 min, then from 5% A+95% B to 95% A+5% B in 3.2 min, then 95%A+5% B for 0.5 min; MS ionization method: ESI⁺

EXAMPLE 15-(2-Fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4-d]pyrimidine

(a) N-(2,4-Dichloro-pyrimidin-5-yl)-4-methoxy-3,5-dimethyl-benzamide

A solution of 3.2 g of 5-amino-2,4-dichloro-pyrimidine in 50 ml of ethylacetate was added to a mixture of 25 ml of a saturated aqueous solutionof sodium hydrogencarbonate and 25 ml of water. Then a solution of 4.9 gof 3,5-dimethyl-4-methoxybenzoyl chloride was added at room temperatureover a period of 15 min. The mixture was mixed intensively for 4 h. Thenthe layers were separated and the aqueous layer was extracted twice withethyl acetate. After drying over sodium sulfate and filtration thesolvent was removed in vacuo to give 7.54 g of raw product. The rawproduct was triturated with 25 ml of isopropanol. After filtration andwashing with 10 ml of isopropanol, 2.74 g of the title compound wereobtained as a white solid.

(b) 5-Chloro-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4-d]pyrimidineA solution of 2.74 g ofN-(2,4-dichloro-pyrimidin-5-yl)-4-methoxy-3,5-dimethyl-benzamide and 3.2ml of N,N-diisopropylethylamine in 17 ml of acetonitrile was split intotwo batches which were each heated for 1 h to 160° C. in a microwavereactor. The batches were then recombined and the precipitate wasisolated by filtration to give 600 mg of the title compound as a darkbut quite pure solid (600 mg). The solvents of the mother liquor wereremoved in vacuo and the residue was subjected to silica gelchromatography (heptane/ethyl acetate gradient) to give another 600 mgof the title compound as a pale yellow solid.

(c)5-(2-Fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4-d]pyrimidine149 mg of sodium hydride were added under an argon atmosphere to asolution of 418 mg of 2-fluoro-phenol in 15 ml of dimethylacetamide.After stirring for 30 min at room temperature, a solution of 900 mg of5-chloro-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4-d]pyrimidine in20 ml of dimethylacetamide was added slowly. The mixture was allowed tostir for 1.5 h at room temperature. Upon consumption of the startingoxazolo[5,4-d]pyrimidine an aqueous solution of citric acid (100 g/l)was added until the pH was neutral. The aqueous layer was extractedtwice with 15 ml of ethyl acetate, and the combined organic layers weredried over sodium sulfate, filtered, and the solvents were removed invacuo. The title compound was isolated by silica gel chromatography(heptane/ethyl acetate gradient). Yield: 820 mg of a white solid.

LC/MS (method LC3): Rt=3.56 min; m/z=366.0 [M+H]⁺

EXAMPLE 24-[5-(2-Fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol

A solution of 510 mg of5-(2-fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4-d]pyrimidinein 20 ml of dichloromethane was cooled to 0° C. Over a period of 10 min,4.2 ml of a 1 M solution of boron tribromide in dichloromethane wasadded. The mixture was stirred at 0° C. for 1 h, and then another 2 mlof a 1 M solution of boron tribromide in dichloromethane were added.After stirring for another 1 h, 10 ml of a saturated aqueous solution ofsodium hydrogencarbonate were added slowly. The aqueous layer wasextracted twice with 15 ml of dichloromethane, and the combined organiclayers were dried over sodium sulfate, filtered. The solvents wereremoved in vacuo to give 445 mg of the title compound as a white solid.LC/MS (method LC2): Rt=3.62 min; m/z=352.13 [M+H]⁺

Analogously to the preparation of the example compounds described above,the example compounds of the formula I listed in Table 1 were prepared.In part, they were obtained in the form of their trifluoroacetic acidsalt.

TABLE 1 Example compounds of the formula I m/z Rt Example Name LC/MS[M + H]⁺ [min] 3 5-(2-fluoro-phenoxy)-2-(3-methoxy-phenyl)- LC1 338.21.29 oxazolo[5,4-d]pyrimidine 44-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin- LC1 324.21 1.232-yl]-phenol 5 5-(2-fluoro-phenoxy)-2-(4-methoxy-3-methyl- LC1 352.221.27 phenyl)-oxazolo[5,4-d]pyrimidine 65-(2-fluoro-phenoxy)-2-(4-methoxy-3- LC1 406.16 1.38trifluoromethyl-phenyl)-oxazolo[5,4-d]pyrimidine 74-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin- LC1 338.15 1.282-yl]-2-methyl-phenol 8 2-(4-methoxy-3,5-dimethyl-phenyl)-5-phenoxy- LC3348.03 3.55 oxazolo[5,4-d]pyrimidine 92-(4-methoxy-3,5-dimethyl-phenyl)-5-(pyridin-3- LC3 349.01 2.78yloxy)-oxazolo[5,4-d]pyrimidine 104-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin- LC1 392.11 1.312-yl]-2-trifluoromethyl-phenol 112,6-dimethyl-4-[5-(pyridin-3-yloxy)-oxazolo[5,4- LC1 335.14 1.15d]pyrimidin-2-yl]-phenol 124-[5-(3-fluorophenoxy)-oxazolo[5,4-d]pyrimidin-2- LC1 380.15 1.38yl]-2-isopropyl-6-methyl-phenol 135-(2-fluorophenoxy)-2-(4-methanesulfonyl-3- LC1 400.1 1.27methylphenyl)-oxazolo[5,4-d]pyrimidine 145-(2-fluorophenoxy)-2-(4-methanesulfonyl-2- LC1 400.12 1.26methylphenyl)-oxazolo[5,4-d]pyrimidine

Determination of the Pharmacological Activity

A) GTP-γ-S assay using human Edg-1 receptors

In order to determine the Edg-1 receptor activation by the compounds ofthe invention, a GTP-γ-S (guanosine 5′-[thio]triphosphate) assay forG-protein coupled receptor binding based on the scintillation proximityassay principle was used, employing a cell membrane preparation from aCHO Flp-In cell line which constitutively overexpresses the human Edg-1receptor.

(a) Cell line generation The Flp-In™ expression system (Invitrogen, cat.no. K6010-01) allows the generation of stable mammalian cell lines intowhich the gene of interest has been integrated through homologousrecombination at a specific genomic location called Flp RecombinationTarget (FRT) site by means of a Flp recombinase encoded by the pOG44expression plasmid. The integration of the pcDNA5/FRT expressionconstruct into the Flp-In host cell line genome results in thetranscription of the gene of interest. The stably transfected cellsbecome hygromycin-resistant.

One day prior to transfection, 200 000 Flp-In-CHO cells were seeded inHam F-12 medium (Invitrogen, cat. no. 31765) supplemented with 10% fetalcalf serum (FCS; Perbio Science, cat. no. SH30068.03) in a 6-well plateand incubated at 37° C./5% CO₂ overnight. Using the FuGENE® 6transfection reagent (Roche, cat. no. 11988387001), cells werecotransfected with the Flp recombinase expression plasmid pOG44 and amodified plasmid additionally containing the edg-1 gene (accession no.NM_(—)001400) termed as pcDNA5-FRT-TO_nFLAG_DEST-EDG-1 with a 9:1 ratio.To obtain the modified pcDNA5-FRT-TO_nFLAG_DEST plasmid, the Invitrogenplasmid pcDNA5/FRT/TO (Invitrogen, cat. no. V6520-20) was adapted to theGateway® (Invitrogen) cloning system by inserting a Gateway cassettecontaining attR recombination sites flanking a ccdB gene and achloramphenicol-resistance gene (Gateway conversion system, Invitrogen,cat. no. 11828-029). In addition a FLAG tag epitope was added before the5′ att recombination site to allow recombinant expression ofN-terminally FLAG-tagged proteins.

For the transfection of one well, 1.08 μg of pOG44 and 0.12 μg ofpcDNA5-FRT-TO_nFLAG_DEST-EDG-1 were mixed to 100 μl of serum-free HamF-12 medium containing 6 μl of FuGENE® 6 transfection reagent. After 20min of incubation, the transfection reagent/DNA complex was distributeddropwise on the cells. The cells were incubated for 24 h at 37° C. Thenthe cells from 3 wells were transferred to a T75 flask (GreinerCellstar®, cat. no. 658175) containing Ham F-12 medium supplemented with10% of FCS but without antibiotic and were incubated another 24 h. 48 hafter transfection, the medium was replaced by selection medium (HamF-12 supplemented with 10% of FCS and 300 μg/ml of hygromycin B(Invitrogen, cat. no. 10687-010)). The medium was exchanged every 2 to 3days until a resistant population of cells had grown. Cells were severaltimes splitted and seeded into a new flask so that the cells did notreach more than 25% of confluency. After 2 weeks of selection, the cellswere transferred into T175 flasks (Greiner Cellstar®, cat. no. 660175)and cultivated for batch production. Cells were harvested from theculture flasks by short treatment (2 to 5 min) with Accutase (PAA, cat.no. L11-007), resuspended in selection medium (see above) andcentrifuged at 200×g for 5 min. Cells were resuspended in a mixture of90% of FCS and 10% of dimethylsulfoxide and stored frozen in liquidnitrogen.

(b) Membrane Preparation

A membrane preparation was obtained by standard methods from theafore-described CHO Flp-ln cell line constitutively overexpressing thehuman Edg-1 receptor. Briefly, the cryopreserved cells were taken inculture and grown until confluency in T175 cell culture flasks (BectonDickinson, cat. no. 35 5001). Cell culture was stopped by washing withcalcium-free phosphate-buffered saline (PBS; Gibco, cat. no. 14190), andcells were harvested with a rubber-policeman in 4° C. cold andcalcium-free PBS supplemented with a protease inhibitor cocktail(complete protease inhibitor; Roche, cat. no. 1697498; 1 tablet per 50ml) and subsequently centrifuged at 4° C. for 15 min at 1100×g (HeraeusMinifuge T). For cell lysis, the pellet was resuspended in a 4° C. coldhypotonic buffer consisting of 5 mM HEPES (Sigma-Aldrich, cat. no.H-0981), 1 mM EDTA (disodium salt; Merck, cat. No. 8418) supplementedwith protease inhibitor cocktail (as above) in which cells were storedfor another 15 min on ice. After lysis, cells were centrifuged at 4° C.for 10 min at 400×g (Heraeus Minifuge T). The pellet was disrupted in aDounce homogenizer, diluted with the supernatant of the previouscentrifugation and subsequently centrifuged at 4° C. for 10 min at 500×g(Heraeus Minifuge T) in order to separate nuclei and still intact cellsfrom the membranes mainly present in the supernatant. The supernatantwas then diluted in hypotonic buffer and centrifuged (Beckmann, AvantiJ251) at approximately 18600×g for 2 h at 4° C. After centrifugation,the membrane pellet was resuspended in a storing buffer consisting of 20mM HEPES; 150 mM NaCl (Merck, cat. no. 6400), 1 mM EDTA (as above)supplemented with protease inhibitor cocktail (as above). The membranepreparation was aliquoted and stored at −80° C. Protein concentration ofthe membrane preparation was determined in a sample by means of acommercial protein assay (Bio-Rad, DC Protein Assay, cat. nos. 500-0113,500-0114, 500-0115).

(c) GTP-γ-S Assay

The Edg-1 membrane preparation obtained in (b) was employed in acommercially available scintillation proximity assay (SPA) kit forG-protein coupled receptor binding from Amersham Biosciences/GEHealthcare (code RPNQ0210), in which ligand-induced binding of³⁵S-radiolabeled GTP-γ-S to the receptor-containing membrane, which isbound to scintillation beads, stimulates the emission of light andallows to quantify the in vitro activity of the Edg-1 agonisticcompound. The assay was performed on a 96-well plate substantiallyaccording to the manufacturer's instructions. Before start of theexperiments, scintillation beads were suspended in a reconstitutionbuffer consisting of Tris-HCl (pH 7.4) supplemented with 0.1% (w/v)sodium azide and subsequently diluted on ice with assay buffer(consisting of 20 mM HEPES, 100 mM NaCl, 1 mM EDTA (as above), 1 mMdithiothreitol (DTT), adjusted to pH 7.4) to a final bead concentrationof 30 mg/ml.

Wells were charged with 10 μl of the specified assay buffer, 10 μl of a100 μM guanosine diphosphate (GDP) solution, and 10 μl of a solution ofthe test compound in assay buffer/dimethylsulfoxide resulting in a finalconcentration of the test compound of 10 μM. For the high controls, 10μl of a solution of sphingosine-1-phosphate (S1P; Sigma, cat. no.S-9666), resulting in a final S1P concentration of 10 μM, and for thelow controls 10 μl of assay buffer, was added into respective wellsinstead of the solution of the test compound. All wells containedequivalent amounts of dimethylsulfoxide. Then 10 μl of a [³⁵S]GTP-γ-Ssolution (4 nM) and the Edg-1 membrane preparation obtained in (b) (15μg membrane proteins in 100 μl of assay buffer) was added to each well.After incubation of the plates at room temperature for 5 min, 50 μl ofthe specified scintillation bead suspension (30 mg/ml) was added. Aftera further incubation period of 45 min at room temperature, plates werecentrifuged for 10 min at 500×g. Quantification of [³⁵S]GTP-γ-S bindingand thus receptor activation was measured by means of a beta counter(MicroBeta, Wallac) over 1 min. Values were background-corrected bysubtraction of the respective low control. All measurements were made intriplicate. The receptor activation by the test compound is expressed inpercent of the respective high control (10 μM S1P; regarded as 100%activation). In Table 2 activations observed with example compounds at10 μM are listed.

TABLE 2 Edg-1 receptor activation by example compounds at 10 μM inpercent of the activation by 10 μM S1P Example % Activation 1 102 2 1153 95 4 83 5 42 6 87 7 115 8 94 9 87 10 107 11 103 12 112 13 120 14 69

It can be seen from the measurement data that the compounds are highlysuitable for wound healing and in particular for treating wound healingdisorders of patients with diabetes.

The invention claimed is:
 1. A compound of the formula I, in any of itsstereoisomeric forms, or a mixture of stereoisomeric forms in any ratio,or a physiologically acceptable salt thereof,

wherein A is chosen from NH, O or S; R¹ is chosen fromC₃-C₇)-cycloalkyl-C_(u)H_(2u)— or Het-C_(v)H_(2v)—, wherein u and v arechosen from 1 or 2, or R¹ is a residue of a saturated or unsaturated,3-membered to 10-membered, monocyclic or bicyclic ring which comprises0, 1, 2, 3 or 4 identical or different ring heteroatoms chosen from N, Oor S, wherein one or two of the ring nitrogen atoms may carry a hydrogenatom or a (C₁-C₄)-alkyl substituent and one or two of the ring sulfuratoms may carry one or two oxo groups, and wherein the residue of a ringis optionally substituted on one or more ring carbon atoms by identicalor different substituents R¹¹; R² is chosen from phenyl or pyridinyl,wherein the ring nitrogen atom of the pyridinyl may carry an oxysubstituent, and wherein the phenyl and the pyridinyl are optionallysubstituted on one or more ring carbon atoms by identical or differentsubstituents R²² R¹¹ is chosen from halogen, (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl, hydroxy, (C₁-C₄)-alkyloxy, oxo,(C₁-C₄)-alkyl-S(O)_(m)—, amino, (C₁-C₄)-alkylamino,di((C₁-C₄)-alkyl)amino, (C₁-C₄)-alkylcarbonylamino,(C₁-C₄)-alkylsulfonylamino, nitro, cyano, (C₁-C₄)-alkylcarbonyl,aminosulfonyl, (C₁-C₄)-alkylaminosulfonyl ordi((C₁-C₄)-alkyl)aminosulfonyl; R²² is chosen from halogen, hydroxy,(C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy, (C₁-C₄)-alkyl-S(O)_(m)—, amino, nitro,cyano, hydroxycarbonyl, (C₁-C₄)-alkyloxycarbonyl, aminocarbonyl,aminosulfonyl, R²³ or R²³—O—; R²³ is a residue of a saturated 3-memberedto 7-membered, monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or4 identical or different ring heteroatoms chosen from N, O or S, whereinone or two of the ring nitrogen atoms may carry a hydrogen atom or a(C₁-C₄)-alkyl substituent and one of the ring sulfur atoms may carry oneor two oxo groups, and wherein the residue of a ring is optionallysubstituted on one or more ring carbon atoms by identical or differentsubstituents R²⁴; R²⁴ is chosen from halogen, (C₁-C₄)-alkyl, hydroxy oroxo; Het is a residue of a saturated, 4-membered to 7-membered,monocyclic heterocycle which comprises 1 or 2 identical or differentring heteroatoms chosen from N, O or S and which is bonded via a ringcarbon atom, wherein the residue of a heterocycle is optionallysubstituted by one or more identical or different substituents chosenfrom fluorine or (C₁-C₄)-alkyl; and m is chosen from 0, 1 or 2, whereinall numbers m are independent of each other; wherein all cycloalkylgroups, independently of each other and independently of any othersubstituents, are optionally substituted by one or more identical ordifferent substituents chosen from fluorine or (C₁-C₄)-alkyl; whereinall alkyl, C_(u)H_(2u), C_(v)H_(2v), alkenyl and alkynyl groups,independently of each other and independently of any other substituents,are optionally substituted by one or more fluorine substituents.
 2. Acompound of the formula I, in any of its stereoisomeric forms, or amixture of stereoisomeric forms in any ratio, or a physiologicallyacceptable salt thereof, as claimed in claim 1, wherein A is chosen fromO or S.
 3. A compound of the formula I, in any of its stereoisomericforms, or a mixture of stereoisomeric forms in any ratio, or aphysiologically acceptable salt thereof, as claimed in claim 1, whereinR² is chosen from phenyl or pyridinyl, wherein the ring nitrogen atom ofthe pyridinyl may carry an oxy substituent, and wherein the phenyl andthe pyridinyl are optionally substituted on one or more ring carbonatoms by identical or different substituents R²².
 4. A compound of theformula I, in any of its stereoisomeric forms, or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof, as claimed in claim 1, wherein A is chosen from O or S; R¹ ischosen from (C₃-C₇)-cycloalkyl-C_(u)H_(2u)— or Het-C_(v)H_(2v)—, whereinu and v are chosen from 1 or 2, or R¹ is a residue of a saturated orunsaturated, 3-membered to 10-membered, monocyclic or bicyclic ringwhich comprises 0, 1, 2, 3 or 4 identical or different ring heteroatomschosen from N, O or S, wherein one or two of the ring nitrogen atoms maycarry a hydrogen atom or a (C₁-C₄)-alkyl substituent and one or two ofthe ring sulfur atoms may carry one or two oxo groups, and wherein theresidue of a ring is optionally substituted on one or more ring carbonatoms by identical or different substituents R¹¹; and R² is chosen fromphenyl and pyridinyl, wherein the ring nitrogen atom of the pyridinylcan carry an oxy substituent, and wherein the phenyl and the pyridinylare optionally substituted on one or more ring carbon atoms by identicalor different substituents R²².
 5. A compound of the formula I, in any ofits stereoisomeric forms, or a mixture of stereoisomeric forms in anyratio, or a physiologically acceptable salt thereof, as claimed in claim1, wherein A is O.
 6. A compound of the formula I, in any of itsstereoisomeric forms, or a mixture of stereoisomeric forms in any ratio,or a physiologically acceptable salt thereof, as claimed in claim 1,wherein A is O; R¹ is chosen from (C₃-C₇)-cycloalkyl-C_(u)H_(2u)— orHet-C_(v)H_(2v)—, wherein u and v are chosen from 1 and 2, or R¹ is aresidue of a saturated or unsaturated, 3-membered to 7-membered,monocyclic ring which comprises 0, 1 or 2 identical or different ringheteroatoms chosen from N, O or S, wherein one or two of the ringnitrogen atoms may carry a hydrogen atom or a (C₁-C₄)-alkyl substituentand one or two of the ring sulfur atoms may carry one or two oxo groups,and wherein the residue of a ring is optionally substituted on one ormore ring carbon atoms by identical or different substituents R¹¹; R² ischosen from phenyl or pyridinyl, wherein the ring nitrogen atom of thepyridinyl may carry an oxy substituent, and wherein the phenyl and thepyridinyl are optionally substituted on one or more ring carbon atoms byidentical or different substituents R²²; R¹¹ is chosen from halogen,(C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy or cyano; R²² is chosen from halogen,hydroxy, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy, cyano, R²³ or R²³—O—; R²³ isa residue of a saturated 3-membered to 6-membered, monocyclic ring whichcomprises 0 or 1 ring heteroatom chosen from N, O or S, wherein one ortwo of the ring nitrogen atoms may carry a hydrogen atom or a(C₁-C₄)-alkyl substituent and one of the ring sulfur atoms may carry oneor two oxo groups, and wherein the residue of a ring is optionallysubstituted on one or more ring carbon atoms by identical or differentsubstituents R²⁴; R²⁴ is chosen from fluorine, (C₁-C₄)-alkyl or hydroxy;and Het is a residue of a saturated, 4-membered to 7-membered,monocyclic heterocycle which comprises 1 ring heteroatom chosen from N,O or S and which is bonded via a ring carbon atom, wherein the residueof a heterocycle is optionally substituted by one or more identical ordifferent substituents chosen from fluorine or (C₁-C₄)-alkyl; whereinall cycloalkyl groups, independently of each other and independently ofany other substituents, are optionally substituted by one or moreidentical or different substituents chosen from fluorine or(C₁-C₄)-alkyl; wherein all alkyl, C_(u)H_(2u) and C_(v)H_(2v) groups,independently of each other and independently of any other substituents,are optionally substituted by one or more fluorine substituents.
 7. Acompound of the formula I, in any of its stereoisomeric forms, or amixture of stereoisomeric forms in any ratio, or a physiologicallyacceptable salt thereof, as claimed in claim 1, wherein A is O; R¹ is aresidue of a saturated or unsaturated, 3-membered to 7-membered,monocyclic ring which comprises 0 or 1 ring heteroatom chosen from N, Oor S, wherein a ring nitrogen atom may carry a hydrogen atom or a(C₁-C₄)-alkyl substituent and a ring sulfur atom may carry one or twooxo groups, and wherein the residue of a ring is optionally substitutedon one or more ring carbon atoms by identical or different substituentsR¹¹; R² is chosen from phenyl or pyridinyl, wherein the ring nitrogenatom of the pyridinyl may carry an oxy substituent, and wherein thephenyl and the pyridinyl are optionally substituted on one or more ringcarbon atoms by identical or different substituents R²²; R¹¹ is chosenfrom halogen, (C₁-C₄)-alkyl or (C₁-C₄)-alkyloxy; R²² is chosen fromhalogen, hydroxy, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyloxy, R²³ or R²³—O—; R²³is a residue of a saturated 3-membered to 6-membered, monocyclic ringwhich comprises 0 or 1 ring heteroatom chosen from N, O or S, whereinone or two of the ring nitrogen atoms may carry a hydrogen atom or a(C₁-C₄)-alkyl substituent and one of the ring sulfur atoms may carry oneor two oxo groups, and wherein the residue of a ring is optionallysubstituted on one or more ring carbon atoms by identical or differentsubstituents R²⁴; and R²⁴ is chosen from fluorine, (C₁-C₄)-alkyl orhydroxy; wherein all cycloalkyl groups, independently of each other andindependently of any other substituents, are optionally substituted byone or more identical or different substituents chosen from fluorine or(C₁-C₄)-alkyl; wherein all alkyl groups, independently of each other andindependently of any other substituents, are optionally substituted byone or more fluorine substituents.
 8. A compound of the formula I, inany of its stereoisomeric forms, or a mixture of stereoisomeric forms inany ratio, or a physiologically acceptable salt thereof, as claimed inclaim 1, wherein A is O.
 9. A compound of the formula I, or aphysiologically acceptable salt thereof, as claimed in claim 1, chosenfrom5-(2-fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4-d]pyrimidine,4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol,5-(2-fluoro-phenoxy)-2-(3-methoxy-phenyl)-oxazolo[5,4-d]pyrimidine,4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-phenol,5-(2-fluoro-phenoxy)-2-(4-methoxy-3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine,5-(2-fluoro-phenoxy)-2-(4-methoxy-3-trifluoromethyl-phenyl)-oxazolo[5,4-d]pyrimidine,4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2-methyl-phenol,2-(4-methoxy-3,5-dimethyl-phenyl)-5-phenoxy-oxazolo[5,4-d]pyrimidine,2-(4-methoxy-3,5-dimethyl-phenyl)-5-(pyridin-3-yloxy)-oxazolo[5,4-d]pyrimidine,or4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2-trifluoromethyl-phenol.10. A compound of the formula I, or a physiologically acceptable saltthereof, as claimed in claim 1, chosen from2,6-dimethyl-4-[5-(pyridin-3-yloxy)-oxazolo[5,4-d]pyrimidin-2-yl]-phenol,4-[5-(3-fluorophenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2-isopropyl-6-methyl-phenol,5-(2-fluorophenoxy)-2-(4-methanesulfonyl-3-methylphenyl)-oxazolo[5,4-d]pyrimidine,or5-(2-fluorophenoxy)-2-(4-methanesulfonyl-2-methylphenyl)-oxazolo[5,4-d]pyrimidine.11. A pharmaceutical composition, comprising at least one compound ofthe formula I as claimed in claim 1 or a physiologically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 12. A process forthe preparation of a compound of the formula I as claimed in claim 1,comprising reacting a compound of the formula II with a compound of theformula III,

wherein the groups A, R¹ and R² in the compounds of the formulae II andIII are defined as in the compounds of the formula I and additionallyfunctional groups can be present in protected form or in the form of aprecursor group, and the group L¹ is a halogen atom or a group of theformula —S(O)-Alk or —S(O)₂-Alk wherein Alk is (C₁-C₄)-alkyl.
 13. Amethod of treating diabetic foot syndrome in a patient in need thereofcomprising administering to said patient a therapeutically effectiveamount of the pharmaceutical composition of claim 11.